AU667479B2 - Treating the oral cavity with ion-channel forming peptides - Google Patents

Description

I

11 OPI DATE 23/02/93 APPLN. ID 23237/92 1 11 IIIIIII 11 li11 AOJP DATE 29/04/93 PCT NUMBER PCT/US92/05757 11111111 I AU9223237 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 93/01723 AtK 37/02, C07K 7/08, 7/10 Al (43) International Publication Date: 4 February 1993 (04.02.93) (21) International Application Number: PCT/US92/05757 (74) Agents: OLSTEIN, Elliot, M. et al.; Carella, Byrne, Bain, Gilfillan, Cecchi Stewart, 6 Becker Farm Road, Rose- (22) International Filing Date: 9 July 1992 (09.07.92) land, NJ 07068-1739 (US).

Priority data: (81) Designated States: AU, JP, European patent (AT, BE, CH, 735,070 25 July 1991 (25,07.91) US DE, DK, ES, FR, GB, GR, IT, LU, MC, NL, SE).

(71)Applicant: MAGAININ PHARMACEUTICALS, INC. Published [US/US]; 5110 Campus Drive, Plymouth Meeting, PA With international search report.

19462 (US).

(72) Inventors: BERKOWITZ, Barry 5 Pinetree Place, Ft.

Washington, PA 19034 JACOB, Leonard 405 Caranel Circle, Penn Valley, PA 19072 6 6 7 4 7 9 (54) Title: PROPHYLAXIS AND TREATMENT OF ADVERSE ORAL CONDITIONS WITH BIOLOGICALLY ACTIVE

PEPTIDES

(57) Abstract A process for preventing or treating an adverse oral condition(s) which comprises administering to a host at least one biologically active peptide or protein. The peptide or protein is an ion channel-forming peptide or protein. The peptides or proteins are effective against bacteria, fungi, or viruses associated with plaque, gingivitis, dental caries, periodontal disease, dental implant infections, and other oral or dental conditions.

WO 93/01723 PCT/US92/05757 if PROPHRLAXIS AiD TREATMENT UF ADVERSE ORAL CONDITIONS WITH BIOLOGICALLY ACTIVE PEPTIDES Ihis application relates to the prevention and treatment of adverse oral conditions. More particularly, this application relates to the prevention and treatment of adverse oral conditions such as peridontal disease, gingivitis, plaque, halitosis, and dental caries, by employing a biologically active peptide.

In accordance with an aspect of the present invention, there is provided a process for preventing and/or treating an adverse dental condition(s) comprising administering to a host at least one biologically active amphiphilic peptide or biologically active protein. The peptide or protein is an ion channel-forming peptide or protein. The composition is administered in an amount effective to prevent or treat adverse oral conditions in a host.

The term "adverse oral conditions" as used herein is intended to mean any condition which adversely affects the oral cavity, including but not limited to teeth, gum, tongue, and the oral mucoa. Such adverse dental conditions include, but are not limited to, plaque; peridontitis, including chronic peridontitis, adult -1- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 peridontitis, and juvenile peridontitis; gingivitis, including acute necrotizing ulcerative gingivitis, halitosis, and dental caries, including root surface caries and superficial caries.

An ion channel-forming peptide or protein or ionophore is a peptide or protein which increases the permeability for ions across a natural or synthetic lipid membrane. B. Christensen et al. PNAS Vol. 85 Pgs.

5072-76 (July, 1988) describes methodology which indicates whether or not a peptide or protein has ion channel-forming properties and is therefore an ionophore.

As used herein an ion channel-forming peptide or ion channel forming protein is a peptide or protein which has ion channel-forming properties as determined by the method of Christensen at al.

An amphiphilic peptide is a peptide which includes both hydrophobic and hydrophilic peptide regions.

The ion channel-forming peptides employed in the present invention are generally water soluble to a concentration of at least 20 mg/ml at neutral pH in water. In addition, the structure of such peptide provides for flexibility of the peptide molecule. When the peptide is placed in water, it does not assume an amphiphilic structure. When the peptide encounters an oily surface or membrane, the peptide chain folds upon itself into a rod-like structure.

-2- SUBSTITUTE SHEET PCT/US92/05757 WO 93/01723 In general, such peptides have at least 7 amino acids, and prefermbly at least 20 amino acids. In most cases, such peptides do not have in excess of 40 amino acids.

The peptide or protein is generally employed in the form of an oral composition for oral hygiene. Such an oral composition may be incorporated into a wide variety of compositions and materials used for oral hygiene purposes, which include, but are not limited to, toothpastes, mouthwashcs, tooth gels, and tooth powders.

Such a compositon may thus be used to treat or prevent periodontal disease, to prevent or reduce plaque, and/or to prevent or treat or reduce dental cAries. The peptide or protein thus may be used to inhibit, prevent, or destroy the growth of bacteria associated with plaque, periodontal disease, dental caries, and other dental or oral diseases or conditicons. Such bactoeria include, but are not limited to Streytococcua mutans, Actinobacillus act inometemcomitana, Eikenella corrodens, Streptococcus salivarius, Actinomices naeslumdii, Streptococcus sanauis, Actinemces viscosus, Veillonella species, Cap!2rj.bacterix species such as Campylobacter sputor, Bacteroides ainnivalis, Caynacyt pjiago nrocies such as Capnocytoobsta Sinaivalis, Wolinella recta, Bacteroides intermedius, Mycoplaama species such an Myeoulasma salivariM, Trenonema species, su~ch an Treponsma dent icola, Peptostreptacoccua micros, Bacteroides -3- SUBSTITUTE SHEET WO93/01723 PCT/US92/05757 forsythus, Fusobacteria species such as Fusobacterium nucleatum, selenomonads such as Selenomonas sputigena, and Bacteroides fragilis. The peptides, may also be employed in inhibiting, preventing, or destroying the growth of Enterobacter cloacae, which is associated with dental implant infections, such as periimplantitis. The peptides may also be used to inhibit, prevent, or destroy the growth of viruses which adversely affect the oral cavity, and of virally-infected cells found in the oral cavity.

The peptides may also be employed to prevent, inhibit, or destroy the growth of fungi in the oral cavity. For example, the peptides may be employed to prevent, inhibit, or destroy the growth of the fungus Candida albicans, which is associated with thrush.

The peptides may also be employed in promoting or stimulating the healing of wounds in the oral cavity.

The term "wound healing" as used herein includes various aspects of the wound healing process.

These aspects include, but are not limited to, increased contraction of wounds in the oral cavity, increased deposition of connective tissue, as evidenced by, for example, increased deposition of collagen in the wound, and increased tensile strength of the wound; i.e., the peptidea increase wound breaking strength. The peptides may also reverse the inhibition of wound healing caused by a depressed or compromised immune system.

-4- SUBSTITUTE SHEET

I

WO 93/01723 PCT/US92/05787 In general, the peptide or protein is administered topically in an amount of from about 2 mg/ml to about mg/ml.

In accordance with a preferred embodiment, the peptide is a basic (positively charged) polypaptide having at least sixteen amino acids wherein the polypeptide includes at least eight hydrophobic amino acids and at least eight hydrophilic amino acids. Still more particularly, the hydrophobic amino acids are in groups of two adjacent amino acids, and each group of two hydrophobic amino acids is spaced from another group of two hydrophobic amino acids by at least one amino acid other than a hydrophobic amino acid (preferably at least two amino acids) and generally by no greater than four amino acids, and the amino acids between pairs of hydrophobic amino acids may or may not be hydrophilic.

The hydrophilic amino acids are generally also in groups of two adjacent amino acids in which at least one of the two amino acids is a basic hydrophilic amino acid, with such groups of two hydrophilic amino acids being spaced from each other by at least one amino acid other than -a hydrophilic amino acid (preferahly at least two amino acids) and generally no greater than four amino acids, and the amino acids between pairs of hydrophilic amino acids may or may not be hydrophobic.

In accordance with a particularly preferred embodiment, ttb polypeptide comprises a chain of at least SUBSTITUTE SHEET 9 WO 93/01723 FC/!9/55 PC-r/US92/05757 four groups of amino acids, with each grotip consisting of Ifour amino acids. Two of the four amino acids in each group are hydrophobic amino acids, and two of the four amino acids in each group are hydrophilic, with at least one of the hydrophiltic amino acids in each group being a basic hydrophilic amino acid and the other being a basic or neutral hydrophilic amino acid.

The hydrophobic amtino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Pro, Val, Trp, Tyr, norleucine (Nie), norvaline (Nva), anld cyclaoxylalanine (Cha). The noutral hydrophilic amino acids may be selected from the class consisting of Asn, Gin, Ser, and Thr. The basic hydrophilic amino acidis may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Her), 2, 4-diaminobutyric acid (Dbu), and p-aminophanylalanine.

Each of the groups of four amino acids may be of the sequence ABMD, BCDA, CDAB, or br.jC, whuerqqn A and B are eoch hydrophobic amino acids and may be the sae or different, one of C or D is a basic hydrophilic amino acid, and the other of C or D is R hasic or neutral hydrophilic amino acid and may be the sme or different.

In a preferred embodiment, the polypmptide chain may comprise 5 or 6 groups of this seqiioncn. In each group, each of A, B, C and D may be the same in some or all of the groups or may be different in som or all of the groups.

SUBSTITUTE SHEET _I _I WO 93/01723 PCT/US92/05757 The polypeptide chain preferably has at least amino acids, and no greater than 50 amino acids. It is to be understood, however, that the polypeptide does not have to consist entirely of the groups described above.

The polypeptide may have amino acids extending from either or both ends of the noted groups forming the polypeptide chain and/or there may be amino acids between one or more of the' at least four groups and still remain within the scope of the invention.

The groups of amino acids may be repeating groups of amino acids, or the amino acids in the vsrious groups may vary provided that in each group of the at least four groups of amino acids there are two hydrophobic and two hydrophilic amino acids as hereinabove noted.

Thus, in a preferred embodiment, the biologically active polypeptide comprises a chain including at least four groups of amino acids, each containing four amino acids. Two of the four amino acids in each group are hydrophobic, e* least one amino acid is basic hydrophilic, and the remaining one is hasic ot neutral hydrophilic, with the polypeptide chain preferably having at least 20 amino acids but no greater than 50 amino acids.

In one embodiment, each of the at least four groups of amino acids which are in the peptide chain is of the sequence A-B-C-D, B-C-D-A, C-D-A-B or D-A-B-C wherein A and B are hydrophobic amino acids, one of C ;r D is a -7- SUBSTITUTE SHEET F i WO 93/0 1723 PCr/!US92/05757 basic hydrophilic amino acid, and the other of C or D is basic or neutral hydrophilic amino acid. The resulting polyrpeptide chain, therefore, may have one of the following sequences: (X Oa (Y 1b (X (Y r(X 3(C-D-A-B) (Y 3 )b

(X

4 )CY 4 )b wherein X1is C-D- or Y is -A or -A-B or

-A-B-C

Xis D-A- or C-D-A- Y is -B-C or B-C-D Fl 2 x is D-A-B- Y is -C-D-A x is A-B-C- Yis -D-A-B a is o or 1; b is o or 1 and n is at least 4.

It is to be understood that the pimptide chain may include amino acids between the hereInAbove noted groups of four amino acids provided that the qpActng between such groups and the charge on the Ameino acids does not change the characteristics of the peptldp chain which provide amphiphilicity and a positive charge and do not advertely affect the folding characteristics of the chain to that which is significantly different from one In SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 which the hereinabove noted group of four amino acids are not spaced from each other.

As representative examples of peptides in accordance with the present invention, there may be mentioned.

I Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser- Lys -Ala-Phe-Ser-Lys -Ala-Phe-Ser- Lys (SEQ ID N:1) II Ala-Phe-Ser-Lyu-Ala-Phe-Ser-Lys-Ala-Phe-Ser- Lys -Ala-Phe-Ser-Lyu-Ala-Phe-Ser-Lys-Ala-Phe- Ser-Lys. (SEQ ID NO:2) III Phe-Ser-Lys-Ala-Phe-Serj Lys-Ale-Phe-Ser-Lys-Ala- Phe-Ser-Lys-Ala- (SEQ ID NO:3) IV Ser-Lyu-Ala-Pho-Ser-Lys-Ala- I Phe-Ser-Lys-Ala-Phe-Ser-Lys -Ala- Phe-Ser-Lys-Ala-Phe- (SEQ ID NO:4) V Lya-Ala-Phe-Ser-Lys-Ala-Phe-Ser-T.ys-Ala-Phe-Ser- Lym-Ala-Phe-Ser (SEQ ID The peptide, may have amino ac~di extending from either end of the chain. For example, the chains may haye a Ser-Lys sequence before the "Ala" end, and/or an Ala-Pb. sequence after the "Lys" end. Other amino acid sequences may also be attached to the "Ala" and/or the end.

Similarly, in any polypeptide chain having at leasnt four groups of amino acids of the sequence as described above, the chaain may have, for example, a C-D sequence -9- SUBSTITUTE SHEET WO 93/01723 PTU9/55 PCT/US92/05757 before rhe fj-st A-B-C-D group. Also other amino acid siquences may be attached to the and/or the end of one of these polypeptide chains. Also there may be amino acids in the chain which space one or more groups of the hereinabove noted four amino acids from each other.

The peptides may be produced by known techniques and obtained in substantially pure form. For example, the peptides may be synthesized on an automatic synthesizer.

Journal of American Chemical Society, Vol. 85 Pages 2149-54(1963). It is also possible to produce such peptide.. by genetic engineering techniques. The codona encoding the amino acids- are known to those skilled in the art, and thus one may construct DNA encoding any of the peptides by accepted techniques, and c1tne such DNA into an expression vehicle such as, for example, a plasmid, and transfect such an exprasnion vehicle into a cell which will express the peptide.

In accordance with another preferred embodiment, the peptide may be a mogainin peptide.

A uagainin peptide is either a maminin such as magainin I, II or III or an anx1ngnp or derivative thereof. The magainin peptides profprably include the following basic peptide structure X1 11- 1 1

-R

1 2

'R

1 3

'R

1 1 1 4 1 2

R

1 1" SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 wherein R 11is a hydrophobic amino acid, R 12is a basic hydrpphilic amino acid; R 3is a hydrophobic, neutral hydrophilic, or basic hydrophilic amino acid;R1 and R 14a are hydrophobic or basic hydrophilic amino acids; R 15 is glutamic. acid or aspartic acid, or a hydrophobic or a basic hydrophilic amino acid, and n is 0 or 1. In a preferred embodiment, R 3is a hydrophobic or neutral hydro~philic amino acid, R 14a is a hydrophobic amino acid, and R is is glutamic acid or aspartic acid.

Thus, for example, a miainin peptide may include the following structure: -12 ,2where X 12is the hereinabove described basic peptide structure and Y 2is M R 12 (ii) R 14-R 12 (iii) R11R 14aR 12 (iv) R 14 'R 11 -R 14 -R 12 where R ill R 1 2 R 14 and R 1 4 a are as previously defined.

A megainin peptide may also hmev the following structure: 12 -z 12 wherein X is an previounly definod and Z is: 12 1 Ci) R 6where R 1 6 is a basic hydrophilic amino acid or asperagine or gluternin.

-11- SUBSTITUTE SHEET WO 93/01723 PTU9/55 PCr/L7S92/05757 (ii) R 16 17 whre R 17 is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid, Preferably, R 17 is a neutral hydrophilic amino acid.

A magainin peptide may also have the following structure: (12a a 2 2 b where X 12 Y 12 and Z 2are as previously defined and a is 0 or 1 and b is 0 or 1.

The th~againin peptides may also include the following basic peptide structure X 1 14

R

11 14 a 12

-R

11 11

R

12 13- R 1 1 -R 1 4 -R 1 2 R 1- 11 -11 12 wherein RillR 1 2 R 13 R 14 1 and R 1&are amino acids as hereinabove described.

The magainin peptide may also include the following structure X 13

Z

13 wherein X1 15 thi hereinabove described basic peptide structure and Z 3is CR 16 n -CR 17) nwherein R ill R 14 9 R 1a R 15 R 16 and R 1 are as hereinabove described, and n is 0 or 1, and each n may be the same or different.

The magainin peptides generally Inclide at lest fourteen amino acids and may includat up to forty amino acids. A magainin peptide preferably has 22 or 23 amino -acids. Accordingly, the hereinabove described basic peptide structures of a magainin peptide may include -12- SUBSTITUTE SHEET WO 93/01723 PTU9/55 PC'T/US92/05757 additional amino acids at the amino end or at the carboxyl end, or at both ends.

As representative examples of such magainin peptides, there may be mentioned peptides having the following primary sequences as given in the accompanying sequence listing as well as appropriate analogues and derivatives thereof: (SEQ ID NO:6) (OH) or (NH 2 (Nagainin I) (SEQ ID NO:7) (OH) or (NH 2 (Nagainin II) (SEQ ID NO:8) (OH) or (NH 2 (Nagainin III) The following are examples of peptide derivatives or analogs of the basic structure: (SEQ ID NO:9) (OH) or (NH 2 I(e) (SEQ ID NO:lO) (OH) or (NH 2 Mf (SEQ ID NO:ll) (OH) or (NH 2 Nagainin peptides are described In Proc. Natl. Acad Sci. Vol. 84 pp. 5449-53 (Aug. 87). The. term 'magainin peptides" an used herein refers to the hnsic magainin structure as well as derivatives mnd mna Jogs thereof, including but not limited to the representative derivatives or analogs.

In accor&Xice with a further embodimont, the peptide may be a PGLa peptide or an XPF peptide.

-13- SUBSTITUTE SHEET WO 93/01723 PCT/ US 92/05757 A PGLa peptide is either PGLa or an analogue or derivative thereof. The PGLa peptides preferably include the following basic peptide structure X, 4 -R 1 -Rl 7 -R 12 R 11 -R 14

R

14 -R l R l- R 1 4 -R 1 2 -R 1 1 -R 1 1

R

1 2

-R

1 1 R11- R 11 127 where R ill R 12 R 14 and R 7are as previously defined.

The PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids. Accordingly, the hereinabove described basic peptide structure for a PGLa putptide may include additional amino acids at the amino end or at the carboxyl end or at both the amino and carboxyl end.

Thus, for example, a PGLe peptide nay have the following structure: -y 1 4 -x 1 4 where X4is as previously defined and 14is Mi R 1 1 (ii)

R

14 -R 1 1 where R and R are as previously defined.

11 14 For example, a PGLa peptide mmy also have the following structure: x 14 z 14 where X4 is as previously defined; and Z4is: Mi R 11 or -14- SUBSTITUTE SHEET WO 9301723PCT/US92/05757 where R is as previously defined.

A PGLa peptide may also have the following structure: (Y4)Xa 1 4

Z

1 4 b where X 1 4 Y1 4 and Z,,are as previously defined, a is 0 or 1 and b is 0 or 1.

An XPF peptide is either XPF or an analogue or derivative thereof. The XPF peptides preferably include the following basnic peptide structure X16 R R -R R -R -R 11 17 12 R 11 14

-R

18 17 11 R 1 4

-R

1 2

-R

1 1 1 1

R

1 2 R -R R R -C(R -R wherein R ill R 12

R

1 4 R 15 and R V are as previously def ined and R 18is glutainie or asparagine or a basic hydrophilic, or hydrophobic amino acid and, n is 0 or 1.

The XPF paptides generally include at least nineteen amino acids and may include up to forty amino acids.

Accordingly, the hereinabove described basic peptide structure of XPF may include additionAl amino acids at the amino end, or at the carboxyl end or at both the amino and carbaxyl ends.

Thus, for example, an XPF peptide may include the following structure: -Y 16X 6 where X 6is as previously defined and Y 6is SUBSTITUTE SHEETr WO 93/01723 PTU9/55 PCT/US92/05757 R 11 or Ri R 14

R

11 where R 11and R 14are as previously defined.

An XPF peptide may include the following structure: -16- 16where X 1 6 is as previously defined and Z 1 6 is W R) or (ii) R is; or (iii) Ri -Ri-Praline; or R i-R Proline-R 12 An XPF peptide may also have the following structure: (16)a- 6( 6 b where X 16 Y 1 6 and Z 6are as previously defined: a is 0Oar 1 and bis 0or 1.

Preferred are XPF or PGLa peptides, which are characterized by the following primary amino acid sequences an given in the accompanying se.qunes listing: PGLa (SEQ ID NO: 12) (NH 2 XPF (SEQ ID NO:13) A review of XPF and PGLa can be found in Hoffman et al, EMDO J. 2:711-714, 1983; Andreit et al, J. Bioche.

149:531-535, 1985; Gibson et al J. Biol. Chan.

261:5341-5349, 1986; and Giovamnint ft al, Bioch.. J.

243:113-120, 1987.

-16- SUBSTITUTE SHEET I* PCI WO 93/01723 PCT/US92/05757 In accordance with yet another embodiment, the peptide may be a CPF peptide or appropriate analogue or derviative thereof.

CPF peptides as well as analogues and derivatives thereof are herein sometimes referred to collectively as CPF peptides.

The CPF peptide may be one which includes the following basic peptide structure X 20 -R21-R21 R22 R22-R21 R21 "23-R21

-R

2 1

"R

2 1

-R

2 3

-R

2 1

R

2 1

-R

2 4

"R

2 5

-R

2 1 wherein R 21 is a hydrophobic amino acid; R22 is a hydrophobic amino acid or a basic hydrophilic amino acid; R23 is a basic hydrophilic amino acid;

R

24 is a hydrophobic or neutral hydrophilic amino acid; and is a basic or neutral hydrophilic amino acid.

The hereinabove basic structure is hereinafter symbolically indicated as X 20 The hydrophobic amino acids are Ala, Cys, Phe, Gly, lie, Leu, Het, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).

The neutral hydrophilic amino acids are Asn, Gin, Ser, and Thr.

The basic hydrophilic amino acids are Lys, Arg, His, Orn, homoarginine (Har), 2,4-diaminobutyric acid (Dbu), and p-aminophenylalanine.

-17- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 The CPF peptide may include only t~v hereinabove noted amino acids or may include additional amino acids at the amino and/or carboxyl end or both the amino and carboxyl end. In general, the peptide does not include more than 40 amino acid.

The CPF peptides including the above basic structure preferably have from 1 to 4 additional amino acids at the amino end.

Accordingly, such preferred peptides may be represented by the structural formula: 0 x wherein X 20 ia the hereinabove described basic peptide structure and Y Mi R 25 or (Wi R 2 2 -R 25 or (iii) R 2 1 -R 2 2 -R 2 5 or (iv) R 2 2 -R 2 1 -R 2 2

-R

2 5 preferably Glycine R 2 1

-R

2 2 -R 25 wherein R 'R2 and R 2 are as previous~ly defined.

The carboxyl end of the basic peptide structure may also have additional amino acids which may range from I to 13 additional aMino acids.

In a preferred embodiment, the basic structure may have from 1 to 7 additional amino Acids At the carboxyl end, which may be represented an follows: -X wherein 20-12- SUBSTITUTE SHEET WO 93/0 1723 PCT/US92/05757 X is the hereinabove defined basic peptide structure andZ R 2 1 or (ii) R 21 R 21 or (iii) R R R;o 21 21

-R

24 ;o (iv) R21- 21 -R 24

R

24 or R 21- 21R 24R 24 -R 26 or (vi) R 21

R

21 -R 24 -R 24 -R 2 Gln; or (vii) R 2-R 2-R 2-R24-R 2-(1ln-Gln, wherein R2 adR24 aeas previous ly defined, and R 26 is proline or 'hydrophobic amino acid.

Preferred peptidem may be represented by the following structural formula a -X20 (Z 20 )b wherein X 0 2)and Z2 are as previously defined and a is 0 or 1 and b is 0 or 1.

Representative examples of CPF peptid~s which may be employed, some of which have bean des~cribed in the literature, include the following sequences as given in the accompanying sequence listing: (SEQ ID 110:14) (SEQ ID 110:15) (SEQ ID 110:16) (SEQ ID 110:17) (SEQ ID NO:18) (SEQ ID NO:19) -19- SUBSTITUTE SHEET WO 93/01723 PCT/ US92/05757 (SEQ ID NO: (SEQ ID NO: 21) (SEQ ID NO:22) (SEQ ID NO:23) (SEQ ID NO:24) (SEQ ID (SEQ ID NO:26) A review of the CPF peptides can be found in Richter, K. Egger, R. and Krail (1986) J. Biol,. Chem 261, 3676-3680; Wakabmyashi, T. Kato, and rachibaba, S. (1985) Nucleic Acids Research 13, 1817-1828; Gibson, B.W., Poulter, William, and Miaggio, J.E. (1986) J.

Biol. Chem 261, 5341-5349.

In accordance with yet another embodiment, the peptide may include one of the foliowing basic structures

X

3 1 through X 37 wherein: x 1is -IR 3 1 -R 3 2 -R 3 2 -R 3 3 -R 3 1 "R 3 2,-R 21'n X 3 is 2R3-R 3-R 31R 32'R 3-R 31n; x32i 3 2

'R

3 33 31 32 32 3131.n x33 i 3-R 3-R 3-R3-R 3- R 32R 32 1-n; x 3 1

-R

3 2 -R 3 2 -R 31 R 3 2

R

3 2

-R

3 3 1-n; x36 is-(R 32

R

32 -R 31

'-R

32

"R

32

R

33 -R 31 1-n and x 7is -(R 32 -R 31 -R 32

-R

32 'R 33

R

31

R

32 1 -n; wherein R 31is a basic hydrophilic Amino acid, R 32 is a hydrophobic amino acid, R 3 3 is a neutral hydrophilie, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to SUBSTITUTE SHEET 8~ 1 WO 93/01723 PCT/US92/05757 The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2,4-diamin'butyric acid (Dbu), and p-aminophenylalanine.

The hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, Pro, Val, Trp and Tyr,norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).

The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser and Thr.

In accordance with one embodiment, when the peptide includes the structure X 31 the peptide may include the following structure: Y31-X31, wherein X31 is as hereinabove described, and Y31 is:

R

3 2 (ii) R 32

-R

32 (iii) R 31

-R

32

-R

32 (iv)

R

33

-R

31

-R

32

-R

32

R

32

-R

33

-R

31

-R

32 -R3 2 or (vi) R 32

-R

32

-R

33 -31-! 32 -R3. whrein R 31

R

3 2 and R33 are as hereinabove described In accordance with another embodiment, when the peptide includes the structure X 31 the peptide may include the following structure:

X

31

-Z

31 wherein X31 is as hereinabove described, and 2 3 is: -21- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 R 31 (iii) R-R 32 32' (ii) R 3 1 -R32-R32 R 1 R -R R R o 3"32- 3 2

-R

3 3

-R

3 1 o (vi) R 3 1 'R 3 2

R

3 2 -R 3- R 3 1 -R 3 2 In accordance with yet another embodiment, the peptide may include the following structure: (Y 3 l)a~x 3 l(Z 3 1)b' wherein Y 31 and Z 31 are as prcefiouely defined, a is 0 or 1, and b is 0 or 1.

When the peptide inraludes the structure X the peptide may inclu~e the following structure: Y32 'x32' wherein X2is as hereinabove described, and Y 32 is: R 3 1 (ii) R -R 3or (vi) k 3 2 'R 3 3

-R

3 1

-R

3 2

-R

3 2

-R

3 1 In another embodiment, when the ppptid" Includeg t~he structure X 32 the peptide may inclside the following strueturs: x 32 z 32 wherein X2is as hetreinAbove described, adZ32 in: Ci) R 32 (ii) R 32

-R

32 -22- 'SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 (iii) R32-R32-R33; (iv)

R

32

-R

32 -R 33-R 31

R

32

-R

32

-R

33

-R

31 3 2 or (vi) R 32

-R

32 -R33-R 31

-R

32

-R

32 In accordance with yet another embodiment, the peptide may include the following structure:

(Y

32 )a -32 (Z 32 wherein Y32 and Z32 are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with another embodiment, when the peptide includes the structure X 3 3 the peptide may include the following structure:

Y

3 3

X

3 3 wherein X 3 3 is as hereinAbove described, and Y33 is: R32; (ii) R31-R32; (iii) R 32

-R

31

-R

32 (iv) R 32

-R

32

-R

31

-R

32

R

3 1

-R

3 2

-R

3 2

-R

3 1

-R

3 2 or (vi) R 33 -R31-R 32

-R

32

-R

31

-R

32 wherein R 31

R

32 and R33 are as hereinabove described.

In accordance with another embodiment, when the peptide includes the structure X 33 the peptide may include the following structure: X33 233 wherein X33 is as hereinabove described, and Z33 is: R32; (ii) R32-R33; -23- SUBSTITUTE SHEET WO 93/01723 PFU9/55 PCr/US92/05757 (iii) R 32

-R

33

R

3 1 (iv) R 3 2

R

3 3

R

3 1

'-R

3 2 (v R 3 2 -R 3 3

R

3 1

R

3 2 -R 3 2 or (vi) R 3 2-R 3 3 -RM 3 3R 32'R 1 In accordance with yet another embodiment, the peptide may include the following structure: (33a- x 3- (Z 3 3 wherein Y 3and Z 33 are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with yet another embodiment, when the peptide includes the structure X 34 9 the peptide may include the following structure: Y x 34 wherein X 4is as hereinabove described, and Y 34is: R32 (ii)R32R32 (iii) R 3 1 -R 3 2 -R 3 2 (iv) R 3 2 -R 3 1 -R 3 2 'R 3 2 R 3 2 -R 3 2 'R 3 1

'R

3 2 -R 3 2 or (vi) R 31 ~i32R 32 -R 31 -R 32 -R 32 9 whflr.In R 3 1 R 32 and R 33are as hereinabove described.

In accordance with another simbodimeint, when the peptide includes the structure X3*the peptide may include the follwing structure: x 4-z 4'wherein X 4is as hereinabove described, and Z 34 in: (i)R33 -24- SUBSTITUTE SHEET PCr/US92/05757 WO093/01723 (ii) R (iii) R 33

-'R

31

-R

32 (iv) R 33

-R

31

-R

32

-R

32 o R~ 3-R 3- R 3-R 3- R 31r 3-R31- 32- 32R 31- 32' In accordance with yet another embodiment, the peptide may include the following struicture: (Y 34)a- X 3 4 (z 34 wherein X 34 and Z 4are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with a further embodiment, when the peptide includes the structure XW 5 the peptide may include the following structure: Y 3 5 -x 35 wherein X 5is an hereinabove described, and Yis: (i)R33 (ii) R 3 2 -R 3 3 (iii) R 3 2

-R

3 2

-R

3 (iv) R 3 1 -R 3 2 -R 3 2 -R 3 3 R 3 2 -R 3 1 'R 3 2

-R

32 -R 33 or (vi) R 3 2 -R 3 2 -R 3-R 32'R 32R3'wherein R1,R3'and R 33are as hereinabove described.

.In accordance with another emhodimant, when the peptide includes the structure X 33 the peptide may include the following structure:

SX

3 Z wherein X 3 is as hereinabove described, and Z R 3 1 SUBSTITUTE SHEET WO 93/01723 PTU9/55 PCT/US92/05757 (ii)R 1R 2 (iii) R3 1 -R 32

R

32 R3-R 3-R32R31 (v 1R 32- 3 2 -R 3 1

R

3 2 or (vi) R 31 R 2

R

32 R 3-R 32 -R32 In accordance with yet another embodiment, the peptide may include the following structure: CY 35 x 35 (Z 35)bP wherein X 5and Z 5are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with a further embodiment, when the peptide inclucdqa the structure X 36 the peptide may include the following structure: Y36 -X 36 wherein X 36is as hereinabove described, and Y 36is: Ci) R31 (ii) R 3 3 'R 3 1 Ciii) R 3 2 -R 3 3 -R 3 1 (iv) R 3 2 'R 3 2 -R 3 3 -R 3 1 R 3 1 'R 3 2 -R 3 2 'R 3 3 -R 3 1 or (vi) R 3 2 -R 3 1 -R 3 2 -R 3 2 -R 3 3 -R 3, where in R 31 R 32 and R 3are an hereinabove described.

In accordance with another embodiment, when the peptide includes the structure X 36 the peptide may include the following structure: x 6 6 herein X 6is as hereinabove described, an' Z 3 is: Ci)R32 -26- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 (ii) R32-R32; (iii) R32-R32-R31; (iv) R 32

-R

32

-R

31

-R

32

R

32

-R

32

-R

31

-R

32

-R

32 or (vi) R 32

-R

32

-R

31

-R

32

-R

32

-R

33 In accordance with yet another embodiment, the peptide may include the following structure:

(Y

3 6)a- X 36 (Z 36)b wherein Y36 and Z36 are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with one embodiment, when the peptide includes the structure X 3 7 the peptide may includes the structure Y 3 7

-X

3 7 wherein X37 is as hereinabove described, and Y37 is:

R

3 2 (ii) R 3 1

-R

3 2 (iii)

R

3 3

-R

3 1

-R

3 2 (iv) R32-R33-R31-R32;

R

3 2

-R

3 2

-R

3 3

-R

3 1

-R

3 2 or (vi) R 3 1

-R

3 2

-R

3 2 -R33-R31"R32, wherein R31, R32, and

R

33 are as hereinabove described.

In accordance with a further embhodiment, when the peptide includes the structure X 3 7 the peptide may include the following structure: X37 Z37 wherein X 3 7 is as hereinabove described, and Z37 is: R32; (ii) R32-R31; -27- SUBSTITUTE SHEET "I'M I- PRO 4P P I PCT/US92/05757 WO 93/01723 (iii) R3-R3- 2 (iv) R 3 2

R

3 1 -R 3 2

R

3 2 R 32

R

31

R

32

R

32 -R 33; or (vi) R 3 2

R

3 1 -R 32

-R

3 2 3- R 3 1 In accordance with yet another embodiment, the peptide may include the following structure: (Y37a. x 37 (Z37b wherein Y 7and Z 3 7 are as previously defined, a is 0 or 1, and b is 0 or 1.

In a preferred embodiment, n is 3, and most preferably the peptide is of one of the following structure3 as given in the accompanying sequence listing: (Lye Ile Ala Gly Lys Ile (Lys Ile Ala Lys Ilie Ala (Lys Ile Ala Gly Lys Ile (Lye Lou Ala Gly Lys Lou (Lye Phe Ala Gly Lye Ph.

(Lye Ala Lou Ser Lye Ala (Lys Lou Lou Lys Ala Lou (Lys Ala Ile Gly Lys Ala (Gly Ile Ala Lye Ile Ala (Lys Ile Ala Lys Ile Ph.

(Gly Ile Ala Arg Ile Ala (Lys Ph. Ala Arg Ile Ala (Gly Phe Ala Lys Ile Ala (Lye Ile Ala Gly Orn Ile (Lye Ile Ala Arg Ile Ala (Orn Ile Ala Gly Lys Ile Ala) 3 Gly) 3 Gly) 3 Ala) 3 Ala) 3 Lau) 3 Gly) 3 Ile) 3 Lye) 3 Gly) 3 Lye) 3 Gly) 3 Ly)3 Ala) 3 Gly) 3 Ala) 3 2a- (SEQ ID NO:27).

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

(SEQ

NO: 28).

NO: 29).

NO: NO:3 1).

NO: 32).

NO: 33).

NO: 34).

NO: NO: 36).

NO: 37), NO: 38).

NO: 39).

NO0:40).

NO: 4 1).

NO: 42).

SUBSTITUTE SHEET WO 93/01723 PF S9/55 PCT/US92/05757 (Gly Ile Ala Arg Ile Phe Lye) 3 (SEQ ID 140:43).

(Lys Nie Ala Gly Lys Nie Ala) 3 (SEQ ID NO:44).

(Lys Nle Ala Gly Lys Ile Ala) 3 (SEQ ID NO:4S).

(Ly Ile Ala Gly Lys Nie Ala) 3 (SEQ rD NO:46).

(Lys Nva Ala Gly Lys Nva Ala) 3 (SEQ ID NO:47).

(Lye Nva Ala Gly Lye Ile Ala) 3 (SEQ ID NO:48).

(Lye Lou Lou Ser Lys Lou Gly) 3 (SEQ ID NO:49).

(Lys Lou Lou Sot Lys Ph. Gly) 3 (SEQ ID (Lys Ile Ala Gly Lys Nvc Ala) 3 (SEQ ID 140:51).

(His Ile Ala Gly His Ile Ala) 3 (SEQ ID 140:52).

(Ala Gly Lys Ile Ala Lys Ile))3 (SEQ ID 140:53).

(Ile Ala Lyse Ala Gly Lye) 3 (SEQ ID 140:54).

(Lyu Ile Ala Gly Arg Ile Ala) 3 (SEQ ID 140:55).

S Ile Ala Gly Arg Ile Ala) 3 (SEQ ID 140:56).

(Lye Val Ala Gly Lye Ile Ala) 3 (SEQ ID 140:57).

(Lys Ile Ala Gly Lye Val Ala) 3 (SEQ ID 140:58).

(Ala Lys Ile Ala Gly Lye Ile) 3 (SEQ ID 140:59).

(Orn Ile Ala Gly Orn Ile Ala) 3 (SEQ ID 140:60).

(Lys Pb. Ala Gly Lys Ile Ala) 3 (SEQ ID 140:61).

(Lys Ile Ala Gly Lys Ph. Ala) 3 (SEQ ID NO:62).

(Lys Cha Ala Gly Lys Ile Ala) 3 (SEQ ID 140:63).

(Lys Ni. Ala Lye Ile Ala Gly) 3 (SEQ ID 140:64).

CArg Ile Ala Gly Lys Ile Ala) 3 (SEQ ID 140:65).

(Har Ile Ala Gly Har Ile Ala) 3 (SEQ TD 140:66).

(Xaa Ile Ala Gly Lye Ile Ala) 3 (SKQ ID NO:67).

(Lys Ile Ala Gly Xam, Ile Ala) 3 (SEQ ID 140:66).

-29- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 Lys Ile Ala (Lys Ile Ala Gly Lys Ile Ala) 3(SEQ ID WO:69).

In (SEQ ID NO: 67) arnd (SEQ ID NO: 68), Xaa is p-aminophenylalanine.

In accordance with another embodiment, the biologically active amphiphilic peptide includes the following basic structure X 40 R31- 3 2 -R 3 2 -R 33 R 34- 3 2 -R 3 2

-R

3 1 -R 32 R32 R32R 34R 32R 32' wherein R 31 t R 32 and R3 are as hereinabove described, and R 34 is a basic hydrophilic or hydrophobic amino acid.

In accordance vith one enbodiment, the peptide may include the following structure: Y40"409wherein X0is as hereinabove described, and Y.is: Mi R 32 (ii) R3- 2 (iii) R 34 "R 32

-R

32 (iv) R 33 -R 34 -R 32

'R

32 R 32 -R 33 'R 34 -R 32

R

32 Cv) R 32 -R 32 -R 33 -R 34

-R

32

-R

32 or (vii) R 31 -R 32 -R 32 -R 33

-R

34

-R

32

-R

32 wherein R 31 1 R 32 R 3and R 34 are an hereinabove described.

In accordance with another embodiment, the peptide may include the fcp1lowing structure: SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT'/US92/05757 x4-z40wherein X 0is at hereinabove described and Z is: 40 (i)R31 (ii)R31R32 (iii) R3- 2 2 (iv) R 3 1 -R 3 2

R

3 2 -R 3 3 R 31

R

32 -R 32

-R

33 -R 34 (vi) R 31

R

32 -R 32 -R 33 'R 34

R

32 or (vii) R 31 'R 32 -R3 2 -R 33 'R 34 -R 32 -R 32 wherein R 31 R 3 2 R 33 and R 34 are as hereinabove described.

In accordance with yet another embodiment the peptide may include the following structure: (Y 4 0)a-x 4 0-(Z 4 0)b) wherein Y 0and Z 0are as previously defined, a is 0 or 1, and b is 0 or 1. In a preferred embodimient, the peptide has the following structural formula as given in thea accompanying sequence listing: (SEq ID In another preferred embodiment, the peptide ties the following structural formula as given In the accompanying sequence listing: (SEQ ID NO:71) In accordance with a further embodimenit, the peptide has one of the one of the following strvictural formulae an given in the accompanying sequence listing: (SEQ ID NO:72) (SEQ ID NO:73) -31- SUBSTITUTE SHEEM WO 93/01723PCiS9/57 PCr/US92/05757 (SEQ ID NO:74) (SEQ ID (SEQ ID NO:76) (SEQ ID NO:77) (SEQ ID NO:7B) (SEQ ID NO:79) (SEQ ID (SEQ ID NO:8l) (SEQ ID NO:82) (SEQ ID NO:83) (SEQ ID NO:54) (SEQ ID (SEQ ID NO:86) (SEQ ID NO:87) In accordance with another embodiment, the peptide may include the following structural formula: (Lys Ile Ala Lys Lys Ile Ala)- n, wherein n is from 2 to 5. Preferably, ni is 3, and the peptide has the following structural formula: (Lys Ile Ala Lys Lye Ile Ala) 3 (SEQ ID NO:8I) -In accordance with another embodiment, the peptide may include the following structural formul&: -(Lys Phe Ala Lys Lys Phe Ala)- n wherein n is from 2 to S.

Preferably, n is 3, and the peptide has the following structural formula: 32- SUBSTITUTE SHEET WO 93101723 ciU2/55 PCr/US92/05757 (Lys Phe Ala Lys Lys Phe Ala) 3 (SEQ ID NQ:89) Ir accordance with another embodiment, the peptide may include the following structural formula; -(Lys Phe Ala Lys Lys Ile Ala)-n wherein n is from 2 to 5. Preferably ni is 3, and the peptide has the following structural formula: (Lys Ph. Ala Lys Lys Ile Ala) 3 (SEQ ID In accordance with another embodiment, the peptide may be selected from the group consisting of the following structural formulae as given in the accompanying sequence listing: (SEQ ID NO:91) (SEQ ID NO:92) (SEQ 7D NO:93) (SEQ ID NO:94) In accordance with yet another embodiment, the peptide may be a cecropin or sarcotaxin.

The term cecropins includes the basic struJcture as well as analogues and derivatives thorrof, The cecropins end analogues and derivatives thereof are described in Ann. Rev. Microbial. 1987, Vol. 41, pages 103-26, in particular page 108, and in Christemen, et PHAS Vol. 85, pg.. 5072-76, which are hereby incorporated by reference.

-33- SUBSTITUTE SHEET WO 93/0 1723 PCT/ US92/05 757 The term sarcotoxins includes the basic materials as we. as analogues and derivatives thereof. The sarcotoxins and analogues and derivatives thereof are described in Molecular Entomology, pages 369-78, in particular page 375, Alan R. Liss, Inc, (1987), which is hereby incorporated by reference, In another embodiment, the amphiphilic peptide includes the following basic structure X 50

R

41 -R 42

R

42 -R 4 l-R 42

-R

42 -R 41 -R 41

R

42

-R

41

-R

41 R 41 is a hydrophobic amino acid, and R 42 is a basic hydrophilic or neutral hydrophilic amino acid.

In one embodiment, the peptide includes the basic tructure Y 50X0 wherein X0is as hereinabove described and Y ois: Ci)

R

41 (ii) R 42 -R 41 or (iii) R 42 -R 42 -R 41 wherein R 41 and R 42 are as hereinabove described.

In one embodiment, R 4 1 is leiicine. In another embodiment, R 4 2 is lysine. Representative examples of peptides in accordance with this aqpect of the present invention include those having the following structures: (SEQ ID NO: CSEQ ID NO: 96) (SEQ ID NO: 97) (SEQ ID NO: 98) -34- SUBSTITUTE SHEETA WO 93/01723 P~T/US92/05757 in accordance with another embodiment, the amphiphilic peptide includes the following basic structure X 2 R 4 2

R

41 -R 42

R

42

-R

41

-R

41 -R 42

R

42

-R

41 -R42 -R 4'wherein R4 is a hydrophobic amino acid and R 42is a basic hydrophilic or neutral hydrophilic amino acid.

In one embodiment R1is leucine. In another embodiment, R 42 is lysine.

In one embodiment, the peptide includes the basi.

structure Y 52

X

52 1 wherein X 52 is as hereinabove described, and Y 2is; R1R (iii) R (iii) 4 1

-R

41

-R

4 2 (iv) R 42 -R 4 l-R 41

"R

42 or

R

42 -R 42

-R

41

-R

41 -R 42 In one embodiment, the peptide may havo the following structure; I Lys Lys L~iu Lou Lys Lys Lou Lys Lys Lflu Lou Lys Lys L&~u Arg Arg is (SEQ ID NO:99) SUBSTITUTE SHEET -1 ,r1 PCri US92/05757 WO 93/01723 In another embodiment, the peptide includes the basic structure X 52'z5,wherein X 2is as hereipb-v described, aii, 5 is: (ii) R1 1 (iii) R4- 1 2 (iV) R 41

R

41

R

42

-R

42 or k.v) R 41 "R 41

R

42 -R 42

R

41 n one embodiment, the peptide following structure: Lys Lau Lys Lya Lou Lou Lys Lys Lou Lys Lys Lau 5 CSEQ ID NO: 100) In another em' a~diment, the peptide may have the Lys Lou Lau Lys may inclu4de the structure: (Y 52 A x 2- (Z 52)bp wherein X S, Y 5 2 and Z 2are as hare illabfove described, and a is 0 ot, 1, and b is 0 or 1.

In aecordam,,a with another embodiment, the peptide includes the, following basic structure X, 4

-R

41

-R

42

-R

42

-R

41

-R

41

-R

42

-R

42

-R

4 l-R 42

-R

42

R

41

-R

4 l-R 42

.R

4

R

43 Isherein R 4 and R 42 are as hereinabove detscribed, andI R 43 is a netural hydrophilic amino acid.

-36- SUBSTITUTE SHEET

'I

L

WO 93/0)1723 PTU9/55 PCr/US92/05757 In one embodiment, the peptide may have the following structure: (SEQ ID NOil01) In another embodiment, the peptide may have the fol lowing structure: (SEQ ID NO: 102) In accordance with yet another embodiment, the peptide includes the following basic structure X R 41

-R

42

-R

41 -R 41 -R 42 'R 42 -R 41 -R 41 -R 42 -R 42

-R

44 1 wherein R4 and R 42are as hereinabove described, and R 44 is a neutral hydrophilic amino acid or praline.

In one embodiment, the peptide may include the following structure Y 5-x 5, wherein X 6is the basic peptide structure hereinabove described, and Y 5 6 is: Mi -R 41 (ii) -R 41 -R 41 (iii) 2R4' 1 (iv) -R 4-R 42R 4-R 41; (v R41R 41' 42R 41R 41; (vi) -R 42

R

41

R

41

R

42 -R 41

R

4 1 -,or (vii) -R 42 -R 42 -R 41

R

41

R

41

R

42

R

41

-R

41 1 wherein R 41 and R 42 are as herainabov" described.

In one embodiment, the peptide may include the structure: x 5 6 z 5 6 wherein X 6is as hereinabove described, and z 6is: Ci -R 4 2 -37- SUBSTITUTE SHEET -MM 1- 11 ell WO 93/01723 PTU9/55 PCr/US92/05757 (ii) 2 2 (iv) -R 4 2

R

4 2

R

4 1

-R

4 1 -R 4 2

-R

4 2

'-R

4 1

-R

4 1

R

4 2 (vi) -R 42 R 4 2 -R 4 1

-R

4 1

R

4 2

R

4 2 or (Vii) -R 4 2

-R

4 2

'-R

4 1

-R

4 1

R

4 2

'-R

4 2

'-R

4 1 In a preferred embodiment, the peptide rray have one of the following structures: (SEQ ID NO:103); or (SEQ ID NO:104).

In another embodiment, the peptide may have the structure (Y 56 )a 5X 6 56 )bl wherein X 56 Y 56 and Z 6are as hereinabove described, a is 0 or 1, and b is 0 or 1.

In accordance with another embodiment, the peptide includes the following basic structure X 5 8: R 41 -R 41 -R 42

-R

42 -R 41 -R 42 -R 42

R

41 -R 4 l-R 42 -R 42 -R 41

R

43 0 wherein R 41 R 42 and R 43 are as hereinabove described.

In accordance with another embodiment, the peptide may include the structure Y 58 -x 5 8, X 58i is as hereinabove described, and Y 5 8 is: (ii) -R 42 -R 41 C(iii) -R 42

'R

42 'R 41 (iv) -R 41 'R 42 -R 42

-R

41 -R 41 'R 41 -R 42 -R 42

R

41 (vi) 42

R

41

-R

41 42

-R

42

R

41 o SUBSTITUTE SHEET i 1 WO 93/01723 PCT/US92/05757 (vii) -R 4 2

-R

4 2

-R

4 1 -R 4

-R

4 2-R-R 4 1 wherein R 4 1 and R 42 are as hereinabove described.

In another embodiment, the peptide includes the structure X 58 -Z 58 wherein X58 is as hereinabove described, and Z58 is: -R41; (ii)

-R

4 1

-R

4 5 (iii) -R41-R 45

-R

45 (iv) -R 41

-R

45

-R

4 5-R 43

-R

41

-R

45

-R

45

-R

4 3

-R

41 (vi) -R 41

-R

45

-R

45

-R

43

-R

41

-R

4 3 (vii)

-R

4 1

-R

4 5 -R45-R4 3

-R

4 1

-R

4 3

-R

4 3 (viii) -R 4 1

-R

4 5

-R

4 5-R 3

-R

4 1

-R

4 3

-R

4 3

-R

4 5 or (ix) -R 41 -R45R 4 5 -R 4 3 -R 41 43-R 43

-R

45

-R

43 wherein R 41 and R 43 are as hereinabove described, and R 4 is proline.

In one embodiment, the peptide has the following structure: (SEQ ID NO:105).

In one embodiment, the peptide may have the structure (Y58)a-X58- (Z58)b, wherein X58, Y58, and Z 5 8 are as hereinabove described, a is 0 or 1, and b is 0 or 1.

In accordance with another embodiment, the peptide includes the following basic structure

X

60

R

41

-'R

4 1

-R

43

R

42

-R

41

-R

41

-R

41

-R

41

-R

41

-R

4 1

-RA

2

-R

41

-R

41

-R

4 2

R

42

-R

4 1 -39- SUBSTITUTE SHEET r I WO 93/01723 PCT/US92/05757 R 1-R 2-R 2-R 2-R 1#wherein R 141 R 42 and R 4 3 are as hereinabove described. In one embodiment, the peptide may have the following structure: (SEQ ID NO: 106).

In another embodiment, the peptide may include the sttucture X6-z0'wherein X 0 is as hereinabove described, and Z (ii) -R4R 2 Ciii)

-R

4 2 -R 4 2 -R 41 (iv) -R 42 -R 42

-R

41 -R 41 -R 4 2 -R 4 2 -R 4 1 -R 4 1 -R 4 2 (vi) -R 42 -R 42R 4-R 41

'R

42

R

42 ;or (vii) -R 42 -R 42 -R 41 -R 41

'R

42 -R 42 -R 1 In accordance with yet another embodiment, the peptide has a structure selected from the group consisting of: R 41 -R 42 -R 42 -R 41 42 -R 41 R 41

-R

41 -R 42 -R 42

'R

41 -R 42

R

42

R

41 Cc) R 42-R 41-R 41 -R 42

-R

42 -R 41

R

42

R

42

R

41 R 42

AR

42 -R 41 -R 41 -R 42 -R 42 "R 41 -R 42

R

42

R

41 and R 41 -R 42 -R 42 -R 41

-R

41

-R

42 -R 42

R

41 -R 42 -R 42 -R 41 wherein R and I are as hereinabovo desceribed.

In one embodiment, the peptIdP hai the structure Ca), and a representative example of such a structure is (SEQ ID NO:107), which is given In the accompanying sequence listing.

~il_ SUBSTITUTE SHEET WO 93/01723 PCF/1S92/05757 In another embodiment, the peptide has the structure and a representative example of such a structure is CSEQ ID NO: 108), which is given in the accompanying sequence listing.

In another embodiment, the peptide has the structure and a representative example of such a structure is (SEQ ID NO: 109) as given the accompanying sequence listing.

In yet another embodiment, the peptide has the structure and a representative example of such a structure is (SEQ ID NO:l1O) as given In the accompanying sequence listing.

In a further embodiment, the peptide hos the structure and representative examples of such a structure are (SEQ ID NO:1ll) and (SEQ ID NO:1l2) as given in the accompanying sequence listing.

In accordance with another embodiment, the peptidie has the following structural formula: (SEQ ID NO: 113).

In accordance with another embodiment, the peptide is malittin.

kieittin is en amphipathic peptide consisting of 26 amino acid residues, and is isolated from honeybee (Apia mellifera) venom. The peptide is known to be cytolytic.

See Habermann, at al.. Home-evier's Zeitschrift Physiol. Chem., Vol. 348, pgs. 37-50 (1987). Ielittin -41- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 has the following structural formula as represented by the three-letter amino acid code: Gly Ile Gly Ala Val Leu Lys Val Leu Thr Thr Gly Leu Pro Ala Leu Ile Ser Trp Ile Lys Arg Lys Arg Gin Gin (SEQ ID NO:114) In another embodiment, the peptide purified in accordance with the present invention is an apidaecin.

The term apidaecin as used herein includes the basic structure as well as analogues and derivatives thereof.

Apidaecins are further described in European Patent Application No. 299,828.

In accordance with yet another embodiment, the amphiphilic peptide or protein may be an ion channel-forming peptide or protein.

Ion chaninel-forming proteins or peptides which may be employed include defensins, also known as human neutrophil antimicrobial peptides (HNP), major basic protein (MBP) of eosinophils, bactericidal permeability-increasing protein (BPI), and a pore-forming cytotoxin called variously perforin, cytolysin, or pore-forming protein. Defensins are described in SSelated, at al., J. Clin. Invest., Vol. 76, pgs.

1436-1439 (1985). MBP proteins are described in Wasmoen, -42i, SUBSTITUTE SHEET SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 et al., J. Biol. Chem., Vol. 263, pgs 12559-12563.

(1988). BPI proteins are described in Ooi, et al, J.

Biol. Cham., Vol. 262, pgs. 14891-14894 (1987). Perforin is described in Henkart, et al., J. Exp. Med., 160: (1984), and in Podack, et al., J. Exp. Med., 160:695 (1984). The above articles are h(reby incorporated by reference.

The term ion channel-forming proteins includes the basic structures of the ion channel-forming proteins as well as analogues and derivatives.

In accordance with yet another embodiment, each of the amino acid residues of the peptide or protein may be a D-amino acid residue or glycine.

It is also to be understood that the peptides or proteins may be administered in combination with one another.

In accordance with another embodiment, the peptides or proteins of the present invention may be employed in combination with an ion having pharmacological properties for the purposes hereinabove described.

An ion having pharmacological properties is an ion which when introduced into a target cell inhibits and/or prevents and/or destroys the growth of a target cell.

Such an ion having pharmacological properties is one Swhich in the absence of an ion channel-forming peptide or protein is unable to cross a natural or synthetic lipid -43edl %W%^M1Mr§ lar -e WO 93/01723 PCT/US92/05757 membrane; in particular a cell membrane, in sufficient amounts to affect a cell adversely.

The peptide or protein and ion having pharmacological properties may be administered as a single composition or in separate compositions, and the single or separate compositions may include additional materials, actives and/or inactives, in addition to the peptide or protein and anti-target ion. As representative examples of ions having pharmacological properties which may be employed, there may be mentioned fluoride, peroxide, bicarbonate, silver, zinc, mercury, arsenic, copper, platinum, antimony, gold, thallium, nickel, selenium, bismuth, and cadmium ions. In one embodiment, the ion having pharamacological properties is a fluoride ion.

The peptide or protein and the ion having pharmacological properties, whether administered or prepared in a single composition or in separate compositions, are employed in amounts effective to inhibit and/or prevent and/or destroy the growth of oral bacteria, or of viruses or fungi which adversely affect the oral cavity. In effect, the ion potentiates the action of the peptide or protein, the amount of ion is effective to reduce the minimum effective concentration of the peptide or protein for inhibiting 1 growth of oral bacteria, fungi, viruses, or -44- SSUBSTITUTE

SHEET

WO 93/01723 PCT/US92/05757 virally-infected cells which adversely affect the oral cavity.

The ion having pharmacological properties is generally employed in a concentration of from about 1 mg/ml to about 10 mg/ml.

As representative examples of administering the peptide or protein and ion having pharmacological properties, the peptide or protein could be administered in an amount of up to about 2% weight to weight and the ion delivered in an amount of about 0.1% to It is also contemplated that, within the scope of the present invention, the peptide may be administered in combination with other oral hygiene agents such as, but not limited to, chlorhexidine (peridex), sanguinarine HC1, antiseptic mouthwashes, tricolsan, etc.

In accordance with another embodiment, the peptides or proteins of the present invention may be administered to a host in combination with an antibiotic selected from the class consisting of bacitracins, gramacidins, polymyxin, vancomycin, teichoplanin. aminoglycosides, hydrophobic antibiotics, penici. nobactams, or derivatives or analogues thereof.

The bacitracins, gramacidins, polmyxin, vancomycin, and teichoplanin, and derivatives ,niogues thereof, are a group of polypeptide antibiotics. A preferred bacitracin is bacitracin A.

SUBSTITUTE SHEET Wo 0 '3PCT/US92/05757 Aminoglycoside antibiotics include tobramycin, kanamycin, amikacin, the gentaniicins gentamicin Cl, gentamicin C 2 gentamicin C la), netilmicin, kanamycin, and derivatives and analogues thereof. The preferred aminoglycosides are tobramycin and the gentamicins. The aminoglycos ides, and the bacitracins hereinabove described, tend to be hydrophilic and water-soluble.

Penicillins which may be employotd include, but are not limited to benzyl penicillin, amptcillin, methicillin (dimethoxyphenyl penicillin), ticaricillin, penicillin V (phenoxymethyl penicillin), oxacillin, cloxacillin, dicloxacillin, flucloxacillin, amoxicillin, and amidinocillin. Preferred penicillins which may be employed are benzyl penicillin and ampicillin. A preferred monobactam which may be employed is aztreonam.

An representative examples of hydrophobic antibiotics which may be used in the prnisent invention, there may be mentioned macrolides such as erythromycin, roxythrowyein, clarithrowycin, etc.; 9-N-alkyl derivative, of erythromycin; midcmyc-in acetate; azithromycin; flurithromycin; rifabutin; rokitamycin; a erythromycin A known sa TE-031 (Taisho); rifeapentine; benzypiperazinyl rifamycins such as CGP-7040, CGP-5909, CGP-279353 (Ciba-Geigy); an erythromycin A derivative with a cyclic carbamate fused to the C 11 /C 12 Pouitioni Of a macrolide ring known an -46- SUBSTITUTE SHEET WO 93/01723 PCT/L'S92/05757 A-62514 (Abbott); AC-7230 (Toyo Jozo); benzoxazinorifamycin; difficidin; dirithromycin; a 3-N-pipeaeinomethylzaino methyl rifamycin SV known as FCE-22250 (Faruitalia); M-l19-a (Kirin Brewery); a 6-O-methyl-l-4"-O-carbamoyl erythromycin known as A-63075 (Abbott); 3-formyirifamycin SV-hydrazones with diazabicycloalkyl side chains such as car-27557 and CGP-2986 (Ciba-Geigy); and 16-membered macrolides having a 3-0-alpha-L-cladinouyl moiety, such as 3-O-alpha-L-cladinosyl-espoxy rosaramicin; tylosins and acyl demycinosyl tylohins.

In addition to the macrolide. hereinabove described, rifamycin, carbenicillin, and nafcillin may be employed as well.

Other antibiotics which may be used (whether or not hydrophobic) are antibiotics which are 50-S ribomome inhibitors such an lincomycin; cIi ndamycin; and chlormphenicol; ae.; antibiotics which have a large lipid like lactone ring, such as mystatin; pimaricin, etc.

The peptide or protein and antibiotic may be adminstered orally in order to pru~vent, destroy or inhibit the growth of bacteria, such as but not limited to those hereinabove described, which may be associated with adverse oral conditions. Bacteria whose growth may be prevented, inhikt',ted, or destroyed by the -47- SUBSTITUTE SHEET -Il;isl l. rrrl~ WO 93/01723 PC/US92/05757 administration of the peptides and antibiotic include Gram-positive and Gram-negative bacteria.

The antibiotic, such as those hereinabove described, or derivatives or analogues thereof, is generally employed in a concetration of about 0.2% to about Peptide or protein dosages may be those as hereinabove described.

The invention will be described with respect to the following examples; however, the scope of the present invention is not intended to be limited thereby.

In the following Examples 1 through 5, the antibacterial activity of various peptides within the scope of the present invention was measured against various oral bacteria by a modiflcatiu.i of the Kirby-Bauer technique (Bauer, at al., Am. J. Clin. Path., Vol. 36, No. 3 (1966), pas. 493-496) in which growth inhibition of the organisms was measured on agar plates seeded with bacterial lawns.

Th2 procedure for determini.g such growth inhibition is as follows: A few colonies if each organism to be tested are picked up with a wire loop and introduced into a test tube containing broth. A broth containing 28g Brucella broth, 2g sodium formate, 3g sodium fumarate, 50 ml defibrinated sheep blood, 2 ml hemolyzed sheep blood cells, 10 ml hemin-menadione solution, and 1 liter of distilled H20 was prepared for the following organisms: -48- SUBSTITUTE SHEET WO 93/01723 P~US92/05757 Eikenella co rod-ens.; Peptostreptococcus micros; Bacteroides intermedius; Bacteroides fraxilis; Bacteroides zingivalis; and Act inomyces via cosus.

The hemin-mettadione iolution used in the above-described broth was prepared by dis~olving 50 ing of hemin in 1 ml 1N NaOH, and brought to 100 ml with distilled H 20 to form a hemin solution. 100 mg of menadione wes adied to 20 ml distilled H 20 to form a menadione solution. 1 ml of the menadione solution is then added to 100 ml o'f the hemin solution to form the hemin-menadione solution 10 ml of which is added to the broth.

A broth containing 22g trypticase soy broth, ig yeast extract, 100 ml horse serum, 5 ml of a bacitracin solution of 75 mig bacitracin in S ml distilled H 0, 3 ml of a vancomycin solution of 5 mg vAncomycin in 5 mil distilled H 0, and 1 liter of distilled 1120 is prepared for Actinobscillus actinomyce aeamitans. A broth containing 37g brain heart infusion, 1 0 R yoeast extract, 2g sodium formats, 3g sodium fumoorate, 0.3g sodium thiosulfate, 0.2g ferrous sulfmtot, 5 ml of a hemin-menadione solution of 2.5 mg/l hamin nnd 0.25 mg/l menadione, a solution of 9 mig vancomycin in 12 nil .49- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 distilled water, and 1 liter of distilled lt,0 was prepared for Wolinella recta.

The tubes are incubated to produce a bacterial suspension of moderate cloudiness. The bacteria-containing broth is then diluted, if necessary, with water or saline solujtion to a density virtually equivalent to that of a 0.5 McFarland standard prepared by adding 0. 5 ml of 1% Bad 2 to 99.5 ml of 1% H SO 2~ 2 4 (0.36N).

The bacterial broth suspension is steeaked evenly in three planes onto the surf ace of the culture medium of to 6 mm in depth, in a Petri dish, with a cotton swab.

An agar medium of 3.0% trypticase say broth, agarose, 2,.5 mg/l hemin, and 0.25 mg/l menad,O, is used for the following ovganisms: jkenella corodensu; Pentostreptocotcus micros; Bacteroidej-xLnsivalis; Bacteroidm frazilis; Bacteroides interaefius; and Act inarnyces viscosus,; and Actiikobacil1lus act inomycatemcoi tons.

A medium containing 52g brmin henrt .infusion, agarose, lOg yeast extract, 2g sodium formate, 3g sodium fumarste, 5 al of a hemin-menadiane solution of 2.5 mg/l hemin and 0.25 mg/l menadion*, and 9 mg vancomycin in 12 SUBSTITUTE SHEET -w WO 93/01723 PCT/ US 92/05757 ml distilled H, 0, 0.3g sodium thiosulfate, and 0,2g ferrous sulfate was used for Wolinella recta, After the inoculum has dried, but no longer than minutes after drying, disks saturated with peptide or peptide and NaF are placed on the agar with flamed forceps or a disk applicator. The disks have been saturated with 20 p1 of a peptide solution to deliver a final dose of from 0.25 pg to 125 pg on the disk or with peptide in the heretofore mentioned dasages and 1,000 ppem NaF. The disks may be laid down in a circle to form an outer ring of about 9 disks, and the remaining disks may be placed in the center.

After oviornight incubation, the zone diameters (including the 6am. disk) are measured on the undersurface of the Petri disk with a ruler or with calipers near the Iagar surface. A it -ding of 6mm indicates no inhibition.

The end point is &ken as the lowest dose causing inhibition of growth as determined by the naked eye.

Examle- 1 In this example, Peptides 1 through 4 zjere tested for the minimal inhibitory concentration (MTC) against A.

act inomyetescomitans strain Y4, Eikenella corrodens, S.

mutans strain 6714, S. sanuius strain M-5, and A.

viscosus strain T14V. Peptide 1 has the following structural formula: (SEQ ID NO;115) Peptide 2 has the following structural form~;la: -51- SUBSTITUTE SHEET WO 93/01723 PTU9/55 PCT/US92/05757 (SEQ ID NO:12) Peptide 3 has the following structural formula: (SEQ ID NO: 116) Peptide 4 has the following strvctural formula: (SEQ ID NO: 117) The results are given below in Table I.

Table I MIC (Mg/mi) Organism Peptide 1 Paptide 2 Peaptide 3 Peptide 4 A. actinomycetencomi tans (Y4) 8 N/A 32 2 E.corrodens 32 128 N/A 4 S. mutans (6714) 32 64 64 16 N/A 32 32 102 A.viscosus 16 64 N/A 32 (TI4V) Example 2 The procedure of Example 1 was reparied to determine the !IIC of peptides 1 through 4 against A.viscosus strain T14, S.mutane, S.sanzius, A.actipomycstecouitans strain Y4, Ecorrodens, facteroides zi pQvaqiu, Wolinella recta strain 371, and lacteioides intersedius. The results are given below in Table II.

-52- SUBSTITUTE SHEET -19 WO 93/01723 PCT/US92/05757 Table Il KTO Wpm Organiism Peptide 1 Peptide 2 Peptide 3 Peptide 4 A. viscosus (T14) 16 32 16,64 16* S.mutans 8 32 32 16 S.sangius 4 128 32 32 A. Actinomyeatemcomitans(Y4) 8 125 128 8 E.corrodens 16 64 32 8 B.gingivalis 32 32 8 4 W.recta(371) 8 4 16 32** B.intermedius 256 64 64 64 *resistant colonies developed.

extremely large zone of inhibition.

Example 3 The MIC of Peptides 1 through 4 alone, and of Peptides 1 through 4 in combination with 1,000 ppo NaF was tested against A.viscosus, gjnzjus strain 114, S.mutans strain 6715, E.corrods strain 28371, A-actinowycatencomitans straiin Y4, B. XinX~ival.!! strain 33277, BDintermadius strain 25611, And W.,~ecta strain 371. Table III gives the MIC of each peptide alone against each organism, while Table IV gives the NIC of each paptide in combination with 1,000 ppm NaF against each organism.

-53- SUBSTITUTE SHEET I -4ftmmw WO093/01723 .PCr/US92/05757 Organism A. viscosus S.sangius(m4) S. mutans (6715) E. corrodens (28371) A. act inomycetemcomitans (Y4) B. gingivalis (33277) B. intermedius (25611) W. recta (371) Peptide 1 16

/A

8 Table III MIC (jag/mi) Peptide 2 Peptide 3 Peptide 4 32 16,64 16 32 32 16 128 32 8 16 64 32 16 128 121 8 4 64 16,32 64 64 -54i-.

SUBSTITUTE S!HIEET WO 93/0172-1Pr S9/55 PCr/US92/05757 Organism Pei A.viscosus S.sangius(M4) S. mutans (6715) E. corrodens (28371) A. actinomycetemcomitans(Y4) B. gingivalis (33277) B. intermedius (25611) W.recta (371) Table TV g/ml) Peptide +4 1,O pptn. )tide I Peptide 2 Pepti~de 3 Peptide 4 44 4 4 8 4 4 4 N/A The above results show that the MYC for the pnptides were markedly decreased in the presene of 1,000 ppm NaF; there does appear to be some kind of interaction between the peptide and NaF against orml bActeria.

Example 4 In this example, peptides 1, 4, 5, 6, and 7 were tested for minimum inhibitory concentrmtinn (NIC) against Bacteraides fratilis.

Peptide 5 has the following striucturr! formula: (SEQ ID NO: ll8)NH 2 SUBSTITUTE SHEET WO 93/01723 PTU9/55 PCr/US92/05757 Peptide 6 has the following structurAl formula: (SEQ ID NO: 119)-NH 2 Peptide 7 has the following structural formula: (SEQ ID NO: 70)NH 2 Table V below gives the zones of inhibition at various concentrations of peptide per disc.

Table V Zones of Inhibition ma Peptide/disc Peptide 0 1- 4 6- 1 2 4 1MM 111mm 16 32 64 Bair 11Imm 12mm 1 effn 12mm 13mm 12mm 1 .Iim 1 1MM 11Mm 7 7mm 9. From the above table, it can be setn that the MIC of Peptide 1 is 16pg/ml, the HIC of Peptide 5 is fivg/sl, the MIC of Peptide 6 is 6 4 pg/ul, snd the MTC of Peptide 7 is 32pg/ml.

Example In this example, peptides 5, 8, 9, and 10 were tested for minimum inhibitory concentrmtion (MIC) against the followiing organisms: Bacteride iigiais,; Bacteraides intermadius; Actinobacillus act inomyeetemcomi tans; Eikene lie corrodens; -56- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 Wolinella recta; Enterobacter cloacae; Actinomvces viscosus; and Peptostreptococcus micros.

Peptide 8 has the following structural formula: (SEQ ID NO:Z7) Peptide 9 has the following structural formula: (SEQ ID NO: 120)-NH 2 Peptide 10 has then following structural formula: (Lys Ile Ala Gly Lys Ile Ala), wherein each amino acid residue is a D-amino acid residue or glycine.

The MIC values for each peptide are given below in Table VI.

-57- SUBSTITUE SHEET WO 93/0 1723 PC/US92/05757 Table VI MIC (ug/ni) Organism Peptide 5 PeptideB Peptide 9 B. gingivalis (33277) 8 4 32 B. intermedius (25611) 32 16 16 A. actinomycetemcomitans(Y4) 16 16 16 E. corrodens (28371) 16 16 16 W.recta (371) 32 16 16 E.cloacae 32 16 8 A.viscosus 32 16 16 P.micros 16 16 32 Peptide The above assay procedure was also followed in which chiorhexidine gluconate was tested for MIC against Enterobacter cloacae. The MIC of chiorhexidine gluconate against Enterobacter cloacae was 128mg/mi. This indicates that Enterobacter cloacae, which is similar to most of the Gram-negative organisms nssociated with periimplantitia, is more sensitive to the peptides hereinabove tested than it is to chiorhexidtne, which is commonly employed in a rinse after denture implant surgery and placement.

Example 6 -58-

I,

4MI 1124m"" 11rc Imulmar rr b "M"M s PCT/US92/05757 WO 93/01723 In this example, saliva, with its native bacterial flora intact, is isolated from a human volunteer, and is then passed continuously over germanium crystals for minutes prior to treatment. Germanium crystals have surface properties similar to tooth enamel. After equilibration of the saliva in the flow system, water, or Peptide 11, also known as (SEQ ID NO:121); Peptide 12, also known as D-(SEQ ID NO:121) (In which each amino acid residue is a D-amino acid residue or glycine); chlorhexidine; or triclosan in a concentration of 0.lmg/ml in water, were applied for a period of seconds, two times per day for three days, After the treatment, the germanium crystals were analyzed for bacterial count, plaque area, plaque score, and extracellular carbohydrate (ex-CHO, which is indicative of bacterial concentration), by use of a Fourier transformed infrared spectrophotometer. The results are shown in Figure 1. As shown in Figure 1, the Peptide 11 and Peptide 12 are more effective agninst bacteria and plaque than chlorhexidine or triclosan.

The above examples indicate that the peptides of h present invention, whether such peptides are ed alone or in combination with other agents sie as, for example, fluoride ions, are effect against oral bacteria associated with pl a, gingivitis, halitosis, dental caries, pa ontal disease, and other adverse oral co tions.

-59- SUBSTUTE SHEET SUBSTITUTE SHEET j I _j I isr rr I UCIII~ Example 7 Biologically active amphiphilic ion channel-forming peptides were tested for their antimicrobial efficacy against oral pathogens. To determine whether the biologically active amphiphilic ion channel-forming peptides were effective against oral pathogens, the minimal inhibitory concentration (MICs) of each peptide was determined using logarithmic phase cultures in a standard microdilution assay as described in detail above on pages 48-51. This screening test is a variation of a screening test introduced in 1966.

A low MIC demonstrates a peptide's effectiveness in a inhibiting bacterial growth. When the bacteria is an oral pathogen associated with dental or oral diseases, the test indicates the peptide's effectiveness at inhibiting the growth of bacteria in the oral cavity.

Using the standard microdilution assay, MICs of over 30 amphiphilic peptides were determined for the oral pathogen Porphyromonas gingivalis. The results of peptides tested against P. gingivalis are given below in Table VII.

Table VII MIC Against P. gingivalis 04 oao O, 400 o a 00 oo o 0e P o o 0 0 0 0 0 00 a 4 a a 0 a ea e* 0 00 0 0 0* *i 04« 4 0 0 0 0 0 *4 a I) 0 4 Peptide MSI-136 MSI-238 MSI-469 2561 256 8 16 FAY-19M-1 32 8 4 W-50 8 2 2 A7A1-28 2 2 2 VAG-4 128 16 8 MIC values are in .ig/ml 20 As indicated by the low MICs, the peptides were effective, albeit at different levels, in inhibiting growth of five strains of P. gingivalis, For example, peptide MSI-238 M137IPS inhibited the growth of strains 2561 and FAY-19M-1 of P. gingivalis at concentrations as low as 8 ig/ml and strains W-50 and A7A1-28 at concentrations as low as 2 p.g/ml.

Other peptides of the present invention were also effective in inhibiting the growth of various strains of P. gingivalis, For example, peptide MSI-469 M135PS-2 inhibited the growth of five strains of P. gingivalis at concentrations of 64 tg/ml or less, while peptide MSI-248 M1455PS was effective at concentrations of 128 [Lg/ml or less. The results show that biologically active amphiphilic ion channel-forming peptides of the subject application do inhibit the growth of oral bacteria associated with dental or oral disease, such as P. gingivalis.

Amphiphilic peptides of the subject application were also tested for their efficacy against other major oral pathogens such as, Actinobacillus actinomycetemcomitans, Prevotella intermedia, Streptococcus mutans, Streptococcus sanguis, and Actinomyces 35 viscosus. For Example, peptide MSI-469 was shown to have antimicrobial activity against P. gingivalis, P. intermedia, S. mutans, S. sanguis, A. actinomycetemcomitans, ":w s L. a r~-rr and A. viscosus, inhibiting growth at concentrations of 2-32 p.g/ml, 1-2 jIg/ml, 4-32jig/ml, 8-16 pig/ml, 2-8 jg/ml, and 8 pg/ml, respectively. Similarly results were obtained with peptides MSI-20 M768P and MSI-124 M450P and P. gingivalis, P.

intermedia, A. actinomycetemcomitans, and A. viscosus. The resulting MICs demonstrated that biologically active amphiphilic ion channel-forming peptides exhibit antimicrobial activity against major oral pathogens by showing that the peptides prevent bacterial growth at low concentrations.

It is to be understood, however, that the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be practiced other than as particularly described and still be within the scope of the accompanying claims.

o a o a f 4 4 0 o 4 4 4 WO 93/01723 PCrl LS92/05757 SEQUENCE LISTING GENERAL INFORMATION: APPLICANT: Berkowitz, Barry A.

Jacob, Leonard S.

(ii) TITLE OF INVENTION: Prophy1ixis and Treatment of Adverse oral Conditions with Biologically Active Peptides.

(iii) NUMBER OF SEQUENCES: 121 (iv) CORRESPONDENCE ADDRESS: ADDRESSEE: Carella, Byrne, Bain, Cilfillan, Cecchi Stewart STREET: 6 Becker Farm Road CITY: Roseland STATE: New Jersey COUXNTRY: USA ZIP: 07068 COMPUTER READABLE FORM: MEDIUM TYPE: 3.5 inch diskette COMPUTER: IBM PS/2 OPERATING SYSTEM: PC-DOS SOFMWAR.E: DW4.V2 (vi) CURRENT APPLICATION DATA: APPLICATION NUMBER: US/07/735,070 FILING DATE: 25-JUL-19g1

CLASSIFICATION:

(vii) PRIOR APPLICATION DATA: APPLICATION NUMBER: 07/73S,070 -61- SUBSTITUTE SHEET vq am i WO 93/01723 PCF/ US92/05757 FILING DATE: 25-JUL-1991 (Viii) ATTORNEY/AGENT INFORMATION: NAME: Distein, Elliot M.

REGISTRATION NUMBER: 24,025 REFERENCE/DOCKET NUMBER: 421250-129(CIP) (ix) TELECOMMUNICATION INFORMATION: TELEPHONE: 201-994-1700 TELEFAX: 201-994-1744 INFORMATION FOR SEQ ID NO:1: SEQUENCE CIARACTERISTICS: LENGTH: 20 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECU?.W TyiE: peptide PUBLICATIO41 INFORMATION: DOt.UMENT NUMBER: W089/11290 FILING DATE% 19-MAY-1989 PUBLICATION' DATE: 30-NOV-19SI (xi) SEQUENCE DESCRIPTION: SEQ ID NO,.l: Ala Phe Ser Lys Ala Ph. Ser Lys Ala Ph.

Ser Lys Ala Ph. 5cr Lys Ala Ph. 5cr Lys INFORMATION FOR SEQ ID NO;2: SEQUENCE CHARACTERISTICSt LENGTH: 24 amino acids TYPE% amino acid

STRANDEDNESS:

-62- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide PUBLICATION INFORMATION: DOCUMENT NUMBER: W089/11290 FILING DATE: 19-MAY-1989 PUBLICATION DATE: 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lye Ala Phe Ser Lye Ala Phe Ser Lye Ala ?he Ser Lye INFORMATION FOR SEQ ID NO:3: SEQUENCE CHARACTERISTICS: LENGTH: 16 amino acids TYPE: amino acid

STRAMMEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide PUBLICATION INFORMATION: DOCUMENT NUMBER: WO89/11290 FILING DATE: 19-MAY-1989 PUBLICATION DATE: 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Phe Ser Lys Ala Phe Ser Lye Ala Phe Ser Lye Ala Phe Ser Lye Ala -63- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 INFORMATION FOR SEQ ID NO:4: SEQUENCE CHARACTERISTICS LENGTH: 20 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide PUBLICATION INFORMATION: DOCUMENT NUMBER: W089/11290 FILING DATE: 19-MAY-1989 PUBLICATION DATE: 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 16 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide PUBLICATION INFORMATION: DOCUMENT NUMBER! W089/11290 FILING DATE: 19-MAY-1989 PUBLICATION DATE: 30-NOV-1989 -64- SUBSTITUTE SHEET WO 93/01723Pi'US2577 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID N0:S: Lys Ala Phe 5cr Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser INFORMATION FOR SEQ ID NO:6: SEQUENCE CHARACTERISTICS LENGTH: 23 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: Magainin I peptide.

PUBLICATION INFORMATION: AUT3OR: Zaaloff, Michael JOURNAL: 'Proc. Nat. Acad. Sci.

VOLUME: 84 PAGES: 5449-5453 DATE: AUG 1987 DOCUMENT NUMBER: US 4810777 FILING DATE: 04-MAR-1987 PUBLICATION DATE: 07-MAR-1989 SEQUENCE DESCRIPTION: SEQ ID NO:6: Oly Ile dly Lys Phe Lau His Ser Ala Gly Lys Ph. Oly Lys Ala Phe Val Gly Glu Ile Met Lys Ser INFORMATION FOR SEQ ID NO:7: SUBSTITUTE SHEET WO 93/01 723 PT S9/55 PCT/US92/05757 SEQUENCE CHARACTERISTICS LENGTH: 23 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE VYPE: peptide (ix) FEATURE: NAME/KEY: Magainin II peptide.

PUBLICATION INFORMATION: A UTH OR: Zasloff, Michael JOURNAL: Proc. Nat. Acad. Sci.

VOLUME: 84 PAGES: 5449-5453 DATE: AUG 1987 DOCUMENT NUMBER: US 4810777 FILING DATE: 04-MAR-1987 PUBLICATION DATE: 07-MAR-1989 (xi) SEQUENCE DESCRTPTION: SEQ ID NO:7: Gly Ile Gly Lys Phe Leu His Ser Ala Lys Lys Phe Gly Lys Ala Phe Val Gly Glu Ile Met Asn INFORMATION FOR SEQ ID NO:8: SEQUENCE CHARACTERISTICS LENGTH: 22 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide -66- Q1 inarir tore auJee I WO 93/01723 PC1T/US92/O5757 (ix) FEATURE: NAME/KEY: Magairiin III peptide.

PUBLICATION INFORMATION: AUTHOR: Zasioff, Michael JOURNAL: Proc. Nat. Acad. Sci.

VOLUME: 84 PAGES: 5449-5453 DATE: AUG 1987 DOCUMENT NUMBER: US 4810777 FILING DATE: 04-MAR-1987 PUBLICATION DATE: 07-MAR-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: Gly Ilie Gly Lys Phe Leu His Ser Ala Lys Lys Phe Gly Lys Ala Phe Val Gly Glu Ile Met Asn INFORMATION FOR SEQ ID NO:9: SEQUENCE CHARACTERISTICS LENGTH: 22 amino acids TYPE: amino acid STRANDEDlESS: TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: magainin peptide.

PUBLICATION INFORMATION: AUTHOR: Zauloff, Michael JOURNAL: Proc. Nat. Acad. Sci., VOLUME: 84 -67- SUBSTITUTE SHEET WO 93/01723 PCr/US92/05757 PAGES: 5449-5453 DATE: AUG 1987 DOCUMENT NUMBER: US 4810777 FILING DATE: 04-MAR-1987 PUBLICATION DATE: 07-MAR-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: Ile Gly Lys Phe Leu His Ser Ala Lys Lys Phe Gly Lys Ala Phe Val Gly Glu Ile Met Asn Ser INFORMATION FOR SEQ 1D NO:1O: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOG;Y, linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KE: magainin peptide.

PUBLICATION INFORMATION: AUTHOR: Zasloff, Michael JOURNAL: Proc. Nat.-Acad. .Sci.

VOLUME: 84 PAGES: 5449-5453 DATE: AUG 1987 DOCUMENT NUMBER: US 4810777 FILING DATE: 04-MAR-1987 PUBLICATION DATE: 07-KAR-1989 -68- SUBSTITUTE SHEET WO 93/01723 PCT/LUS92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1O: Gly Lys Phe Lau His Ser Ala Lys Lys Phe Gly Lys Ala Phe Val Gly 1lu Ile Met Ann Ser INFORMATION FOR SEQ ID NO:11: SEQUENCE CHARACTERISTICS LENGTH: 20 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEfY: maqainin peptide.

PUBLICATION INFORMATION: AUTHOR: Zaaloff, Michael JOURNAL: Proc. Nat. Acad. Sci..

VOLUME: 84 (1r) PAGES: 5449-5453 DATE: AUG 1967 DOCUMENT NUMBER: US 4810777 FILING DATE: 04-MAR-1987 PUBLICATION DATEZ: 07-MAR-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:ll: Lys Phe Lou His Ser Ala Lys Lys Phe Gly Lys Ala Ph. Val Gly Glu Ii. Mat Ann Ser INFORMATION FOR SEQ ID NO:12: -69- SUBSTITUTIE SHEET WO 93/01723 WO 9301723PCT/US92/05757 Wi SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: PGLa peptide.

PUBLICATION INFORMATION: AUTHOR: Hoffman, et al.

JOURNAL: EMBO J.

VOLUME: 2 PAGES: 711-714 DATE: 1983 AUTHOR: Andreu, et al.

JOURNAL: Journal of Biochemistry VOLUME: 149 PAGES: 531-535 DATE: 1985 AUTHOR: Gibson, et al.

JOURNAL:.J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 AUTHOR: Giovannini, et al.

JOURNAL: Biochem J.

VOLUME: 243 PAGES: 113-120 DATE: 1987 SUBSTITUTE

SHEET

I i WO 93/01723 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Gly Met Ala Ser Lys Ala Gly Ala Ile Ala Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu INFORMATION FOR SEQ ID NO:13: SEQUENCE CHARACTERISTICS LENGTH: 25 amino acids J TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: XPF peptide.

PUBLICATION INFORMATION: AUTHOR: Hoffman, et al.l JOURNAL: EMBO J.

VOLUME: 2 PAGES' 711-714 DATE: 1983 AUTHOR: Andreu, et al.

JOURNAL: Journal of Biochemistry VOLUME: 149 PAGES: 531-535 DATE: 1985 AUTHOR: Gibson, et al.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 AUTHOR: Giovannini, et al.

-71- SUBSTITUTE SHEET WO 93/01723 ~iU9/55 PCr/US92/05757 JOURNAL: Biochem J.

VOLUMIE: 243 PAGES: 113-120 DATE: 1987 -72- SUBSTITUTE SHEET WO 93/01723 P~U9/55 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: Giy Trp Ala Ser Lys Ile Gly Gin Thr Leu Gly Lys Ile Ala Lys Val Gly Leu Lys Ciu Leu Ile Gin Pro Lys INFORM.ATION FOR SEQ ID NO:14: SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: iine~r (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Krei JOURNTL: J. Biol. Chemn.

VOLUME: 261 PAGES: 3676-3680 ((DATE: 1986 AUTHOR: Wakabaymahi, T

JOURNAL:

VOLUME:

PAGES:

DATE:

AUTHOR*.

Kato, H.

Tachibaba, S.

Nucleic-Acids.Research 13 1817-1828 1985 Gibson, B.W.

-73- SUBSTITUTE SHEET WO 93/01723 PCr/US92/05757 Poulter, L, Williams, D.H.

Maggio, J.E, JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 DOCUMENT NUMBER: W090/04407 FILING DATE: 16-OCT-1989 PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: CIly Phe Gly Ser Ph. Leu Gly Leu Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Aen Ala Leu Gly Gly Ala Pro Gln Gln INFORMATION FOR SEQ ID SEQUENCE CHARACTE ISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix. FEATURE: NAME/KEY; CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Richter, K Egger, R.

Kreil JOURNALs J. Bioli Chem.

-74- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 VOLUME: 261 FACES: 3676-3680 DATE: 196 AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 16J17-1828 DATE: 1985 AUTTHOR: Gibson, B.W.

Poulter, Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 DOCUMENT NUMBER: W090/04407 FILING DATE: 16-OCT-1989 PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID Cly Leu Ala Ser Ph. Leu Gly Lys Ala Leu S L~ys Ala Cly Leu Lys Ile Cly Ala His Leu Leu Cly Cly Ala Pro Gin Gin INFORMATION FOR SEQ ID NO:16: SEQUENCE CHARACTERISTICS LENGViZ: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear SUBSTITUTE SHEET r

I

WO 93/01723 PCT/US92/05757 (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY:- CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreil JuJLrNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 3676-3680 DATE: 1586 AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibsoni, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1936 DOCUMENT NUMBER: W090/04407 FILING DATE: 16'.OCT1989 PUBLICATION DATE: 03-MAY-1990 -76- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCr/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu Lys Ala Gly Leu Lys Ile Gly Thr His Phe 1s Lau Gly Gly Ala Pro Gin Gin INFORMATION FOR SEQ ID NO:17: SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreil JOURNAL: J. Biol. Chem, VOLUME: 261 PAGES: 3676-3680 DATE: 1986 AUTHOR: Wakabayeshi, T.

Kate, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibson, B.W.

-77- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 DOCUMENT NUMBER: W090/04407 FILING DATE: 16-OCT-1989 PUBLICATION DATE: 03-MAY-1990 d (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: Gly Leu Ala 5cr Leu Leu Gly Lys Ala Leu Lys Ala Thr Leu Lys Ile Gly Thr His Phe Leu Gly Gly Ala Pro Gin Gin INFORMATION FOR SEQ ID NO:1B: SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECtL"E TYPE: peptide (ix) FEATURE: NAM/KEY: CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Ricehter, K.

Egger, R.

Kreil JOURNAL: J. Biol. Chem.

-78- SUBSTITUTE SHEeT WO 93/01723 PCr/US92/05757 VOLUMThE: 261 PAGES: 3676-3680 DATE: 1986 AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1965 AUTHOR: Gibson, B.W.

Poulter, L.

(D)ER VOLUME:4261 cay(H)i DOCUMNN UM~:BER:h t W0900440 (I)FILNGDATE: 16-OCT-1989 ()PUBLICATION DATE: 03-MAY-1990 EQO NERESRITION:FO SEQ ID NO:18: LENTH 272io0cd ()TYPE: amino acid

()STRANDEDNESS:

()TOPOLOGY: linear -79- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT/US92/65757 (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KCEY: CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreil JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 3676-3680 DATE: 1986 AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 DOCUMENT NUMBER: W090/04407 FILING DATE: 16-OCT-1989 PUBLICATION DATE: 03-MAY-1990 SUBSTITUTE SHEET WO 93/01723 riU9/75 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys A].a Ala Leu Lys Ile Gly Ala Asn Ala 1s Leu Gly Gly Ala Pro Gin Gin INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreil JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 3676-3680 DATE: 1986 AUTHOR: Wakabayshi, T

JOURNAL:

VOLUME:

PAGES:

DATE:

AU*,T-PR Kato, H.

Tachibaba, S.

Nucleic Acids Research 13 1817-1828 1985 Gibson, B.W.

-81- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT/L1S92/05757 Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 DOCUMENT NUMBER: W090/04407 FILING DATE: 16-OCT-1989 PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ser Pro Gir. Gin INFORMATION FOR SEQ ID NO:21: SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANOEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (x-FEATURE: NAME/KEY: CPF peptide.

()PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreil JOURNAL: J. Biol. Chem.

-82- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 VOLUME: 261 PAGES: 3676-3680 DATE: 1986 AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 DOCUMENT NUMBER: W090/04407 FILING DATE: 16-OCT-1989 PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Gly Phe Ala Ser Phe Leu Gly Lyu Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Leu Leu Gly Gly Thr Pro Gin Gin INFORMATION FOR SEQ ID NO:22: SEQUENCE CIARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear -83- SUBSTITUTE SHEEr WO 93/01723 WO 9301723PCT/US92/05757 (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/=E: CPF peptide.

PUBLICATION

CA) AUTHOR:

JOURNAL:

VOLUME:

PAGES:

DATE:

AUTHOR:

JOURNAL:

VOLUME:

PAGES:

DATE:

AUTHOR:

JOURNAL:

VOLUME:

PAGES:

DATE:

INFORMATION:

Richter, K.

Egger, R.

Kreil J. Biol. Chem.

261 3676-3680 1986 Wakabayashi, T.

Kato, H.

Tachibaba, S.

Nuicleic Acids Research 13 1817- 1828 1985 Gibson, B.W.

Poulter, L.

Williams, D.E.

Maqie, J.E.

3. Biol. Chem..

261 5341-5349 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: Gly Ph. Ala Sor Ph. Lou Gly Lys Ala Lou Lys Ala Ala Lou Lys Ile Gly Ala Ann Ala Leu Cly Gly Ala Pro Gin Gin -84- SUBSTITUTE SHEET WO 93101723 ciU9/57 PCI'/US92/05757 INFORM'ATION FOR SEQ ID NO:23: SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: CPF peptide.

PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreil JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 3676-3680 DATE: 1986 AUTHOR: Walcabayashi, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibso~n, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Cheq.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 -as- SUBSTITUTE SHEET WO 93/01723 PI 29/55 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: Gly Phe Ala Ser Phe Leu dly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Met Leu Cly Gly Ala Pro Gin Gln INFORMATION FOR SEQ ID NO:24: SEQUENCE CHARACTERISTICS LEN GTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: x) PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreil JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 3676-3680 DATE: 1986 AUTHOR: Wakabayauhi, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibson, B.H.

-86- SUBSTITUTE SHEET WO 93/01723Pi/U9075 PC'r/US92/05757 Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. '6ioi. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Aan Ala Leu Cly Gly Ser Lau Gin Gin INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: CPF pelotide.

PUBLICATION INFORMATION: AUTHOR: Richter, K.

Egger, R.

Kreii JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 3676-3680 DATE: 1966 SUBSTITUTE SHEET n-_l I _I _J WO93/01723 PCT/US92/05757 AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys Ala Gly Leu Lys Ile Gly Thr Asn Phe Leu Gly Gly Ala Pro Gin Gln INFORMATION FOR SEQ ID NO:26: SEQUENCE CHARACTERISTICS LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: NAME/KEY: CPF peptide.

-88- SUBSTITUTE SHEET ap I -140 IN 1 1 1 -1 0 p -02 IM51-Rpt" M "I mw 0k'"""vRqp WO 93/01723 PCT/US92/05757 PUBLICATION INFOR14ATION: AUTHOR: Richter, K Egger, R.

Kreil JOURNAL: J. Biol. Chem.

VOLUME: 261 PAGES: 3676-3680 DATE:- 1986 AUTHOR: Wakabaymani, T.

Kato, H.

Tachibaba, S.

JOURNAL: Nucleic Acids Research VOLUME: 13 PAGES: 1817-1828 DATE: 1985 AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

JOURNAL: Biol. Chem.

VOLUME: 261 PAGES: 5341-5349 DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: Cly Leu Ala Ser Leu Lou Gly Lys Ala Leu Lys Ala Ala Lou Lys Ile Gly Ala Asn Ala Leu (-ly Gly Ser Pro Gin Gin 2S' INFORMATION FOR SEQ ID NO:27: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid 89- SUBSTITUTE SHEET MVIMMOM91.1 WO 93/01723 P-iU9/55 PCr/US92/05757

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile INFORMATION FOR SEQ ID NO:28: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: Lys Ile Ala Lys Ile Ala dly Lys Ile Ala Lye Ile Ala Gly Lys Ile Ala Lye Ile Ala dly INFORMATION FOR SEQ ID NO:29: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECU,.E TYPE: peptide SUBSTITUTE SHEET ~s.

WO 93/01723 WO 9301723PCT/ US 92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: Lys Ile Ala Giy Lys Ile Gly Lys Ile Ala Gly Lys Ile Gly Lys Ile Ala Gly Lys Ile Gly INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Lys Lau Ala Gly Lys Leu Ala Lys Leu Ala Gly Lys Leu Ala Lys Lau Ala Gly Lys Lou Ala INFORMATION FOR SEQ ID NO:31: SEQUENCE CHARACTERI STICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31! Lys Phe Ala Gly Lys Phe Ala Lys Phe Ala -91- SUBSTITUTE SHEET WO 93/01723 PCf/ US92/05757 Gly Lys Phe Ala Lys Phe Ala Gly Lys Phe is Ala INFORMATION FOR SEQ ID NO:32: SEQUENCE CHARACTIERISTICS LEN GTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: Lys Ala Leu Ser Lys Ala Leu Lys Ala Leu Ser Lys Ala Leu Lys Ala Le"i Ser Lys Ala Leu INFORMATION FOR SEQ ID NO:33: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TY1PE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: Lys Leu Leu Lys Ala Leu Gly Lys Leu Leu Lys Ala Leu Gly Lys Leu Leu Lys Ala Leu is Gly -92- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCr/US92/05757 INFORMATION FOR SEQ ID NO:34: Bi) ROURN82 feHAKAeY!RfflY8bU LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: Lys Ala Ile Cly Lys Ala Ile Lys Ala Ile Cly Lys Ala Ile Lys Ala Ile Gly Lys Ala Ile INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LEN GTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Gly Ile Ala Lyu Ile Ala Lys Gly Ile Ala Lys Ile Ala Lys Gly Ile Ala Lys Ile Ala is Lys INFORMATION FOR SEQ ID NO:36: SEQUENCE CHARACTERISTICS LE~NGTH: 21 asnino acids TYPE: amino acid 93- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: Lys Ile Ala Lys Ile Phe Gly Lys Ile Ala Lys Ile Phe Gly Lys Ile Ala Lys Ile Phe Gly INFORMATION FOR SEQ ID NO:37: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: Gly Ile Ala Arg Ile Ala Lys Gly Ile Ala Arg Ile Ala Lys Oly Ile Ala Arg Ilie Ala is Lye INFORMATION FOR SEQ ID NO:38: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEVNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide -94- SUBSTITUTE SHEET PCr/US92/05757 WO 93/01723 PFU9/55 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: Lys Phe Ala Arg Ile Alai Gly Lys Phe Ala Arg Ile Ala Gly Lys Phe Ala Arg Ile Ala Gly INFORMATION FOR SEQ ID NO:39: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: Gly Phe Ala Lys Ile Ala Lyu Gly Phe Ala Lys Ile Ala Lys Gly Phe Ala Lys Ile Ala Lys INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) (ix) MOLECULE TYPE: peptide

FEATURE.

OTHER INFORMATION: Xaa is ornithine SUBSTITUTE SHEET ~il_ I'o&p- I I %J A Q QM QQ WO 93/01723 PCT/US92/05757 (Xi) SEQUENCE DESCRIPTION: SEQ ID Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala S Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile Ala INFORMATION FOR SEQ ID NO:41: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ TD NO:4l: Lys Ile Ala Arg Ile Ala Gly Lys Ile Ala Arg Ile Ala Oly Lys Ile Ala Ar Ile Ala Gly INFORMATION FOR SEQ ID NO:42: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRNDMEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is ornithine -96- SUBSTITUTE SHEET I n jn.9a WO 93/01723 PCr/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:43: SEQUENCE CHARACTERISTICS LENGTH: 21 aminr acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: Gly Ile Ala Ar Ile Phe Lys Gly Ile Ala Arg Ile Phe Lys Gly Ile Ala Ar; Ile Phie 2 Lys INFORMATION FOR SEQ ID NO:44: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is norleucine.

-97- SUBSTITUTE SHEET M, 'It" R"-pw WO 93/01723 WO 9301723PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa Al a C2) INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ilie Ala Lys Xaa Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:46: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: -98- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCTI US92/05757 OTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SE ID NO:46: Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala Cly Lys Xaa INFORMATION FOR~ SIEQ ID NO:47: SEQUENCE CHARACTZRISTICS LENG!,M: 21 amino acid.

TYPE: amino acid

SIRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FETURE: OTHER INFORMATION: Xaa is norva line.

(xi) SEQUENCE E')ESCRIPTIOII: SEQ ID NO:47: Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala Gly Lys X&% Ala INFORMATION FOR SEQ ID NO:48: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptida -99- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 (ix) FEATURE: OTHER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: Lys Xaa Ala Gly Lys Ile A13 Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala Gly Lys Xaa Ala INFORMATION FOR SEQ ID NO:49: SEQUENCE CHARACTERISTICS LEN GTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49; Lys Leu Leu Ser Lys Lau Gly Lys Leu Leu Scr Lys Leu Gly Lye Leu Leu Ser Lys Leu 1s? Gly INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STEANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPEt peptide -100- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:SO: Lys Leu Leu Ser Lys Phe Gly Lys Le.u Leu Ser Lys Phe Gly Lys Leu Leu Ser Lys Phe Gly INFORMATION FOR SEQ ID NO:51: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amuino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION; Xaa is norvaline.

(xi) SEQUENCE DESCRIPTIOW~ SEQ ID NO:51: I Lys Ile Ala (.1y Lys Xaa Ala Lye Ile Ala 5 113 Gly Lys Xaa Ala Lys Ile Ala Gly Lys Xaa Ala INFORKNTION FOR SEQ ID NO:52: SEQUEI.0,'2 CHARACTERISTICS LENGTH: 21 amino acids Tf'PE: amino acid

STRANDSDNESS:

TOPOLOGY i linear J1 (ii) MOLECULE TYPE: peptide -101- SUBSTITUTE SHEET WO 93/01723 PCr/US92/0575'7 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52; His Ile AIa Gly His Ile Ala His Ile Ala Gly His Ile Ala H~s Ile Ala Gly His Ile Ala INFORMATI.ON FOR SEQ ID NO:53: SEQUENCE CHARACTERISTICS LENGTH- 21 amino acids TYPEt amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ TD NO:53: Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Oly Lys Ile Ala Lys Ile INFORMATION FOR SEQ ID NO:54: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: line.ar (ii) MOLECULE TYPE: peptide -102- SUBSTITUTE SHEET (f ~WO 93/01723 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lays INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STR.ANDEDNESS:

TOPO1oOG;Y: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID li Lys Ile Ala Gly Arg Ile Ala Lys Ile Ala Gly Arg Ile Ala Lys Ile Ala Gly Arg Ile i5 Al a INFORMATION FOR SEQ ID NO:56: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: Arg Ilm Ala Gly Arg Ile Ala Arg Ile Ala -103- SUBSTITUTE SHEET WO 93/01723 WO 93/1 723PCT/US92/05757 Cly Arg Ile Ala Arg Ile Ala Gly Arg Ile Al a INFORMATION FOR SEQ ID NO:57: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY- linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: Lys Val Ala Gly Lys Ile Ala Lys Val Ala Gly Lys Ile Ala Lyu Va1 Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:58: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SFQ ID Lys Ile Ala Gly Lys Va1 Ala Lys Ile Ala 52 'I -Gly Lye Val Ala Lys Ile Ala Gly Lys Val Ala -104- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT/US92/05757 INFORMATION FOR SEQ ID NO: 59: SEQUENCE CHARACTERISTICS LEN GTH: 21 amino acids TYPE: amino acid

STRA?,DEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Giy Lys Ile Ala Lys Ile Ala Gly Lys Ile INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is ornithine.

SEQUENCE DESCRIPTION: SEQ ID Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile Z, Ala INFORMATION FOR SEQ ID NO: 61: -los- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT/US92/05757 SEQUENCE CHARACTERISTICS LEN GTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: Lys Phe Ala Gly Lys Ile Ala Lys Phe Ala ill) Gly Lys Ile Ala Lys Ph. Ala Oly Lys Ile Ala INFORMATION FOR SEQ ID NO:62: SEQUENCE CHARACTERI STICS LENGOTH 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: Lys Ile Ala Gly Lys Phe Ala Lys Ile Ala Gly Lys Phe Ala Lys Ile Ala Gly Lys Ph.

Ala INFORMATION FOR SEQ ID NO:63: SEQUENCE CHARACTERI STICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

-106- ISUBSTITUTE SHEET' r_ I C~ L ~P ~311 Llll"l~ L~ "I~11 *11~01- WO 93/01723 P~/US92/05757 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is cyclohexylalanine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:63: Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:64: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:64: Lys Xaa Ala Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala Gly INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 21 AMINO ACIDS -107- WO 93/01723 WO 9301723PCr/US92/05757 TYPE: amino acids

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6S: Arg Ile Ala Gly Lys Ile Ala Arg Ile Ala Gly Lys Ile Ala Arg Ile Ala dly Lye Ile Al a INFORMATION FOR SEQ ID NO:66: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is homoarginine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:66: Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile Ala (2)INFORMATION FOR SEQ ID NO:67: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid -108- SUBSTITUTE SHEET WO 93/01723 PCT/US92/OS757

STRPYI'DEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: Xaa is p-aminophenylalanine (xi) SEQUENCE DESCRIPTION: SE ID NO:67: Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala dly Lys Ile Ala Xaa Ile Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:68: SEQUENCE CHARACrERISTICS LENGTH: 21 amino acids TYPE: amino acid ST1RhN-DEDNESS: TOPOLOGY: linear MOLECULE TYPE: peptide (ix) FEATURE: Xaa in p-aminophenylaianine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68: Lys Ile Ala Gly Xaa Ile Ala Lyn Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile Ala INFORMATION FOR SEQ ID NO:69: SEQUENCE CHARACTERISTICS: LENGTH: 24 amino acids TYPE: amino acid -109- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757

STRANDEDNESS:

i TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala is Gly Lys Ile Ala INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRAIIDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Lys Leu Ala Ser Lys Ala Gly Lys Ile Ala Gly Lys Ile Ala Lys Val Ala Lou Lye Ala Leu INFORMATION FOR SEQ ID NO:71: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide has- SUBSTITUTE SHEET WO 93/01723 PC'/US92/05757 (ix) FEATURE: OTHER INFORMATION: Xaa is ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:71: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:72: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Arg Ile Ala Lys Ile Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO 7:: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is norleucine.

-111- SSUBSTITUTE SHEET lt._i

I

WO 93/01723 WO 9301723PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:74: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:74: Lys Ile Ala Gly Lyu Ile Ala Lye Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Lye Ile Ala INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: aminio acid

STRANDKDNESS:

TOPOLOGY: linear (ii) MOLEC ULE TYPE: peptide (ix) FEATURE: -112- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCTFiUS92/05757 OTHER INFORMATION: Xaa is ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ TD Lys Phe Ala Cly Lys Phe Ala Lys Phe Ala Gly Xaa Phe Ala Lys Phe Ala Cly Lys Phe Ala INFORMATION FOR SEQ ID NO:76: i) SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:76: Lye Ile Ala Gly Lye Phe Ala Lys Ile Ala Cly Xaa Phe Ala Lys Ile Ala Gly Lys Phe is Ala INFORMATION FOR SEQ ID NO:77: SEQUENCE CHARA CTE RISTICS LENGTH: 21 amino acids TYPE: amino acid STRAI4DEDNESS: TOPOLOGY: linear (ii) MOLECULE TYPE: peptide -113- SUBSTITUTE SHEET WO093/01723 PCT/US92/05757 (ix) FEATURE.

OTHER INFORMATION: Xaa at residues 6, 13, and is norleucine; Xaa at residue 12 is ornithine.

r (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77: Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala Gly Xaa Xaa Ala Lys Ile Ala Gly Lys Xaa Al a INFORMATION FOR SEQ ID NO:78: SEQUENCE CHARACTERISTICS LEN GTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:.

Lys Met Ala Ser Lys Ala Gly Lys Ile Ala Gly Lys Ile Ala Lyu Val Ala Lau Lys Ala is Lau INFORMATION FOR SEQ ID NO:79: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid LI STRANDEDNESS: TOPOLOGY: linear (ii) MOLECULE TYPE; peptide -114- SUBSTITUTE SHEET WO 93/01723 WO 93/1723 Cri US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79 Lys Ile Ala Ser Lys Ala Gly Lys Ile Ala Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS LENGTH t 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linoar (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORMATION: Xaa is norleuc$.ne.

(xi) SEQUENCE DESCRIPTION: SEQ ID Lys Ile Ala Ser Lys Ala Gly Lys Xaa Ala Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu INFORMATION FOR SEQ ID NO:81.

SEQUENCE CHARAC=rISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS;

TOPOLOGY: linear (iii MOLECULtE T'7PTE; peptide (ix) FEATURE: OTHER INFORMAT1JN: Xaa is norleucine.

-115- SUBSTITUJTE SHEET WO 93/01723 PCTI US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81: Lys Leu Ala Ser Lys Ala Gly Lyz Xaa Ala Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu INFORMATION FOR SEQ TO NO%82; SEQUENCE CHARAGCERISTICS LENGTH: 21 amino acids TYPE: amino acid STRAN~vDEDNESS.; TOPOLOGIY: linear (ii) MOLECULE TYPEz peptide (ix) FEAT'JRE,.

(CYTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID :82: Lys Xaa Ala Ser Lys Ala Gly Lys Xaa Ala Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu INFORMATION FOR SEQ ID N0~:83: SEQUENCE CHARACTER,STXCS: LENGTF: 21 amino agida TYPE: amino acid

STRANDEDNESS;

TOPOLOGY: linear (ii) W.C'eECULE TYPE,, peptide (in) FEATURE: OTHER INFORMATI0Nt Xaa in p-amirwpheriylalanine.

SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83: Lys ILe Ala Gly Lys Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile Aia INFORMATION FOR SEQ ID NO:84: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: lineLr (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84: Lys Ile Ala Gly Ala Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide -117- SUBSTITUTE SHEET 11" on"AMMOMM.-Mm WO093/01723 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Ala Ile Ala Lys Ile Ala Gly Lys Ile is Ala INFORMATION FOR SEQ ID NO:86: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Ala Ilie Ala INFORMATION FOR SEQ ID NO:87: SEQUENCE CNVi,,,CTERISTICS: A) L EN Gt 21 amino acids TYPE: amino acid

STR.AIDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87: Lys Leu Ala Ser Lys Ala Ala Lys Ile Ala Ala Lys Ile Ala Lys Val Ala Lau Lys Ala SUBSTITUTIE SHEETA WO 93/01723 PCrl US92/05757 Leu INFORMATION FOR SEQ ID NO:88: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88: Lys Ile Ala Lys Lys Ile Ala Lys Ile Ala Lys Lys Ile Ala Lys Ile Ala Lys Lys Ile Ala INFORMATION FOR SEQ ID NO:89: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE:, peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89: Lys Ph. Ala Lys Lys Ph. Ala Lys Ph. Ala Lys Lys Phe Ala Lys Phe Ala Lys Lys Phe Al a INFORMATION FOR SEQ ID -119- SUBSTITUTE SHEET WO 93/01723 PCr/US92/05757 SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID Lys Phe Ala Lye Lye Ile Ala Lyu Phe Ala Lys Lys Ile Ala Lye Phe Ala Lys Lys Ile Ala INFORMATION FOR SEQ ID NO:91: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:gi: Ala Ile Ala Gly Lye Ile Ala Lys Ile Ala Cly Lys Ile Ala Lys Ile Ala Gly Lye Ile Ala INFORMATION FOR SEQ ID NO:92: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear -120- SUBSTITUTE sIkET WO 93/01723 WO 9301723PCT/US92/05757 (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92: Lys Ile Ala Oly Lys Ile Ala Ala Ile Ala Gly Lys Ile Ala Lys Ile Ala Cly Lys Ile Ala INFORMATION FOR SEQ ID NO:93: SEQUENCE CHARACTERISTICS LENG'TH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Ala Ile Ala Gly Lys Ile Ala INFORMATION FOR SEQ ID NO:94: SEQUENCE CHARACTERISTICS LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) TIOLECULE TYPE: peptide -12 1- SUBSTITUTE SHEET WO093/01723 PCF/ US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94: Gly Met Ala Ser Lys Ala Gly Lys Ile Ala Gly Lys Ile Ala Lys Val Ala Leu Lys Ala 1s Leu INFORMATION FOR SEQ ID SEQUENCE CHARA CTE RISTICS LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID Leu Lys Lys Lau Lys Lys Leu Leu Lys Leu Leu INFORMATION FOR SEQ ID NO:96: SEQUENCE CHARACTERISTICS LENGTH: 12 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:96: Leu Lou Lys Lys Lou Lys Lye Leu Lea: Lye Leu Leu INFORMATION FOR SEQ ID NO:97: -122- SUBSTITUTE SHEET WO 93/01723 PCT/ US92/05757 SEQUENCE CHARACTER.ISTICS: LENGTH: 13 amino acids TYPE: amino acid

STRANDE:DNESS:

TOPOLOGY: linear (ii) MOLECULE 7Z7PE: peptide (xi) SEQUENCL DESCRIPTION:SEQ ID NO:97: Lys Lau Lau Lys Lys Leu Lys Lys Leu Leu Lys Leu Leu INFORMATION FOR SEQ ID NO:98: SEQUENCE CHARACTERISTICS: LENGTH: 14 amino acid.

TYPE: amino acid

STR.ANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:98: Lys Lys Leu Leu Lys Lys Lou Lys Lye Leu Lau Lye Leu Lou INFORMATION FOR SEQ ID NO:gg: SEQUENCE CHARACTERISTICS: LENGTH: 16 rzmino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear -123- SUBSTITUTE SHEET WO 93/01723 WO 931723Prl US92/05757 (ii) MOLECULE TYPE: peptide (ix) SEQUENCE DESCRIPTION: SEQ ID N0:99: Lys Lys Leu Leu Lys Lys Lou Lys Lys Leu Leu Lys Lys Leu Arg Arg INFORMATION FOR SEQ ID NO:100: SEQUENCE CHARACTERISTICS: LENGTH: 16 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION:SEQ ID NO:100: Lys Lou Lys Lys Leu Lau Lys Lys Leu Lys Lys Lou Lou Lys Lou Lou is INFORMATION FOR SEQ ID NO:1O1: SEQUENCE CHARACTERISTICS LENGTH: 15 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide SEQUENCE DESCRIPTION: SEQ Lou Lys Lys Lou Lou Lys Lye Lou Lye Lou Lou Lye Lys Ann is ID NO: 101: Lye -124- SUBSTITUTE SHEET WO093/01723 PCT/US92/05757 INFORMATION FOR SEQ ID NO:102: SEQUENCE CHARACTERISTICS LENGTH: 15 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATUJRE- OTHER INFORMATION: Xaa is homoserine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:102: Leu Lys Lys Leu Lau Lys Lys Lou Lys Lye Lasu Leu Lys Lye Xaa INFORMATION FOR SEQ ID NO:103: SEIPUENCE CHARACTERISTICS LENGTH: 18 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103: Leu Lye Lou Lou Lys Lys Lau Lou Lys Lys Ann Lye Lys Lou Lou Lys Lye Lou INFORMATION FOR SEQ ID NO:104: SEQUENCE CHARACTERISTICS LENGTH: 18 amino acids TYPE: amino acid -125- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT/US92/05757

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104: Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Pro Lys Lys Leu Leu Lys Lys Leu INFORMATION FOR SEQ ID NO:105: SEQUENCE CHARACTERISTICS LENGTH: 22 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: lir.ar (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105; Leu Leu Lys Lys Lou Lys Lyu Leu Leu Lys Lys Leu Gin Gly Pro Pro Gin Giy Gin Ser is Pro Gin INFORMATION FOR SEQ ID NO:106: SEQUENCE CTIARACTERISTICS LENGTH: 20 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide -126- SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1O6: Leu Ala Ser Lys Ala Cly Ala Ile Ala Gly Lys Ilie Ala Lys Lys Leu Leu Lys Lys Leu INFORMATION FOR SEQ ID NO:107: SEQUENCE CHARACTERISTICS LENGTH: 7 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide, (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107: Leu Lys Lys Leu Lys Lys Lou INFORM4ATION FOR SEQ ID NO:108: SEQUENCE CHARACTERISTICS LENGTH: 8 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108: Leu Lou Lys Lys Lou Lys Lys Lou INFORMATION FOR SEQ ID NO: 109: SEQUENCE CHARACTERISTICS LENGTH: 9 amino acids TYPE; amino acid

STRANDEDNESS:

-127- SUBSTITUTE SHEET WO 93/0 1723 PCT/US92/05757 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109: Lys Leu Leu Lys Lys Lau Lys Lys Leu INFORMATION FOR SEQ ID NO:l1O: SEQUENCE CHARACTERISTICS LENGTH: 10 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESChi ZTION: SEQ ID NO:11O: Lys Lys Leu Leu Lye Lys Leu Lys Lys Leu INFORMATION FOR SEQ ID NOz111: SEQUENCE CHARACTERISTICS LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECUE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111! Lau Lys Lys Lou Lou Lys Lys Lou Lye Lye Leu INFORMATION FOR SEQ ID NO:112: SEQUENCE CHARACTERISTICS -125- SUBSTITUTE SHEET WO 9:V01723 PCi! US92/05757 LENGTH: 11 amino acids TYPE: amino aoid

STMANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUEVI.E DESCRIPTION: SEQ ID NO:112: Ala Lys Lys Lev Leu Lys Lye Lou Lys Lys Leu INFORMATION FOR SEQ ID NO: 113: (ii SEQUENCE CH1RACTAISTICS LENGTHI: 14 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOG;Y: linear (ii) MOLECUILE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113: Leu Lys Lys Lou Leu Lys Lye Leu Lye Lye Lou Lou Lys Arg INFORMATION FOR SEQ ID NO:114:.

SEQUENCE CHARACTERISTICS; LENGTH: 26 alutno acids TYPE: amino acid STRA)MEDNESS t TOPOLOCt> linear (ii) MOLECULE TYPE: peptide (Vi) ORIGINAL SOURCE ORGANISM: Api,. mellifera -129- SUBSTtTUTE SHEET WO 93/01723 PMTUS92/05757 (vii) FEATURE: NAME/KEY: melittin peptide PUBLICATION INFORMATION: AUTHORS: Habermani, E.

Jentsch, J.

TITLE: Sequenzanalyse des Melittins aus den tryptischen and peptischen Spa ltstucken JOURNNL: Hoppe-Seyler's Zeitschrift Physiol. Chem.

VOLUM4E: 3 48 PAGES: 37-50 DAT1E: 1987 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11.4: Gly Ile Gly Ala Val Leu Lyr, Val Leu Thr Ile Thr Gly teu Pro Ala Leu Ile Ser Trp Lys Arg Lys Arg Gin Gin INFORMATION FOR SEQ ID NO:i115: SEQUENCE CHARACTERISTICS LENGTH: 22 amino acids TYPE: amino acid

STRANDIVDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide -130- SUBSTITUTE SHEET WO 93/01723 PCr/US92/05757 (xi) SEQUENCE DESCRIPTION: Cly Ile Gly Lys Phe Leu His Ser Lys Phie Gly Lys Ala Phe Val Lys Lys Ser SEQ ID NO: Ala Gly Ile Met INFORMATION FOR SEQ ID NO:116: SEQUENCE CHARANCTERISTICS: LENGTH: 26 amino acids TYPE: amino acid STRnWDEDNESS: TOPOLOGY: linear (ii) MOLECULE TYPE: peptide -131- SUBSTITUTE SHEET WO 93/01723 WO 9301723PCT/ US 92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116: Phe Ala Ser Phe Leu Gly Lys Ala. Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Leu Leu is Gly Gly Thr Pro Gin Gin INFORMATION FOR SEQ ID N~O:117: SEQUENCE CHARACTERISTICS: LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117: Oly Phe Ala Lys Phe Leu Gly Lys t~a Leu Lys Ala Al~a Leu Lys Ile Cly Ala Asn Leu Leu Giy Gly Thr Pro Gin Gin INFORMATION FOR SEQ ID NO:11S: SEQUENCE CHARACTERISTICS: LENGTH: 22 amino acids TYPE: amino acids

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: OTHER INFORM4ATION: amide-termninated SUBSTITUTE SHEET

~A

WO 93/01723 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118: Gly Ile Gly Lys Phe Leu Lys Lys Ala Lys Lys Phe Gly Lys Ala Phe Val Lys Ile Met Lys Lys INFORMATION FOR SEQ ID NO:119, SEQUENCE CHARACTER I SICS: LENGTH: 35 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: amide-terminated -133- SUBSTITUTE. SHEET WO 93/01723 WO 9301723PCT/US92/05757 (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:119; L ys Trp Lys Leu Phe Lys Lys Ile Arg Asn Cly Ile Val Lys Ala Cly Glu Lys Pro Ala 25 Val Gly Arg Asn Cly Ile Ala Val Leu Ala Leu Ala Leu Ala Leu INFORM4ATION FOR SEQ ID NO:120: SEQUENCE CHARACTERISTICS: LENGTH: 22 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: paptide (xi) FEATURE.

OTHER INFORMATION: amide- terminated (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120: Gly Ile Gly Lye Phe Leu Lys Lys Ala Lys Lys Phe G3y Lye Ala Phe Val Lye Ile Leu Lys Lys INFORMATION FOR SEQ ID NO:121: SEQUENCE CHARACTERISTICS: LENGTH: 22 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide SUBSTITUTE SHEET WO 93/01723 PCT/US92/05757 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121: Gly Ile Gly Lys Phe Leu Lys Lys Ala Lys S Lys Phe Ala Lys Ala Phe Val Lys Ilie Ile Asn Asn -135- SUBSTITUTE SHEET

Claims (16)

1. A method for treating an adverse oral condition caused by a bacteria selected from the group consisting of Streptococcus mutans, Streptococcus sanguis, Actinobacillus actinomycetemcomitans, Eikenella corrodens, Actinomyces viscosus, Porphyromonas (previously Bacteroides) gingivalis, Prevotella (previously Bacteroides) intermedius, Bacteroides fragilis, Wolinella recta, Enterobacter cloacae, and Peptostreptococcus micros, in a host in need of such prevention or treatment, comprising: administering to said host a therapeutically effective amount of at least one biologically active amphiphilic peptide or protein, said peptide or protein being an ion channel-forming peptide or protein optionally mixed with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant to form a composition thereof.

2. The method of Claim 1 wherein said peptide or protein is selected from the group consisting of: a magainin peptide; a PGLa peptide; an XPF peptide; a CPF peptide; a cecropin; a sarcotoxin; 20 a peptide including one of the following basic structures X 3 1 through X 37 wherein: X 3 1 is -[R 3 1 -R 3 2 -R 32 -R 3 3 -R 3 1 -R 3 2 -R 32 X 32 is -[R 32 -R 32 -R 33 -R 3 1 -R 32 -R 32 -R 31 X 33 is -[R 32 -R 33 -R 31 -R 32 -R 32 -R 3 1 -R 32 25 X 34 is -[R 33 -R 3 1 -R 32 -R 32 -R 3 1 -R 32 -R 32 X 35 is -[R 31 R 3 -R 3 2 2-R 3 1 -R 32 -R 32 -R 33 X 36 is -[R 3 2 -R 3 2 -R 3 1 -R- 3 2 -R 3 2-R 3

3-3fn-; and X 37 is -[R 3 2 -R 3 1 -R 3 2 -R 32 -R 33 -R 3 1 -R 32 wherein X 3 1 is a basic hydrophilic amino acid, R 32 is a hydrophobic amino acid, 30 R 33 is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to a peptide including the following basic structure X 40 R3 1 -R 32 -R 32 -R 33 -R 33 -R 32 -R 32 -R 3 1-R32-R32-R32-R34-R32-R32, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid; a peptide including the following basic structure X 50 rw.I I-AnAnfI'in VM I p.- WO 93/01723 PCT/US92/05757 R41-R42-R42-R41 42-R424141-R R4 42-R41-R41' wherein R 4 1 is a hydrophobic amino acid, and R 42 is a basic hydrophilic or neutral hydrophilic amino acid; a peptide including the following basic structure X 52 R 42 -R 41 -R 42 -R 42 -R 41 -R 41 42 -R 42 -R 41 R 4 2 -R 42 wherein R 41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid; a peptide including the following basic structure X 54 -R 41 -R 42 R 42 -R 41 -R 41 -R 42 -R 42 -R 41 -R 42 -R 42 -R 41 -R 41 R42 -R 43 wherein R41 is a hydrophobic amino acid, R2 is a 42 42 -R 43 41 P 42 basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid; a peptide including the following basic structure X56' R41-R42R41R41~IR4R4R41-R414 44 wherein R 41 is a hydrophobic amino acid, R42 is a basic hydrophilic cr neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline; a peptide including the following basic structure X 5 8 IR41-R41-RR4p 1 2-R42-R4l-R4l42-R42-R4l43' wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R 43 is a neutral hydrophilic amino acid; a peptide including the following basic structure -R41-R 4 1 -R 4 3 -R 4 2 -R 4 1 -R 4 1 -R 4 -R 4 1 -R 4 1 -R 4 1 -R 4 2 -R 4 1 4 1 2R42R42-R4-R41-R42-R4242-R241, wherein R4 1 is a hydrophobic amino acid, R4 2 is a basic hydrophilic or neutral hydrophilic amino acid, and R; 3 is a neutral hydrophilic amio acid; a peptide having a structure seVl&eted from the group consisting of: 4 ,R 42 -R 42 -R 41 -R 42 -R 42 -R 41 (ii) R 41 -R 4 -R4 2 42 -R 41 -R 42 -R 42 -R 4 1 (iii) R 42 -R 41 4 1 4 2 -R 42 -R 41

4-R 42 -R 4 2 -R 4 1 (ivi) R *R RF R *R -R -R R -R R n 42 421 41- 412 42 421 412 42- 421; (iv) R 42 -R 42 -RP 41 R 4 1 -R 42 -R 42 -R 41 -R 42 42 -R 4 1 and R 4 1 -R 4 2 -R 4 2 -R 4 1 -R 4 1 -R 4 2 -R 4 2 -R 4 -R 4 2 -R 42 -R 4 1 wherein R4 1 is a hydrophobic amino acid, and R4 2 is a basic hydrophilic amino acid or a neutral hydrophilic amino acid: -137- SUBSTITUTE SHEET L melittin; apidaecins; defensins; major basic protein of eosinophils; bacterial permeability-increasing protein; and perforin. 3. The method of claim 2 wherein the peptide is a magainin peptide. 4. The method of claim 2 wherein the peptide is a PGLa peptide. The method of claim 2 wherein the peptide is an XPF peptide.

6. The method of claim 2 wherein the peptide is a CPF peptide.

7. The method of claim 2 wherein the peptide is a cecropin.

8. The method of claim 2 wherein the peptide is a sarcotoxin.

9. The method of claim 2 wherein the peptide includes any one of the following basic structures X 31 through X 37 wherein: X 31 is -[R 3 1 -R 32 -R 3 -R 3 3 -R 3 1 -R 32 -R 32 X 32 is -[R 32 -R 32 -R 33 -R 3 1 -R 32 -R 32 -R 3 1]n- X 33 is -[R 32 -R 33 -R 3 1 -R 32 -R 32 -R 31 -R 32 1C; X 34 is -[R 33 -R 3 1 -R 32 -R 32 -R 3 1 -R 32 -R 32 X 35 is -[R 3 1 -R 32 -R 32 -R 3 1 -R 32 -R 32 -R 33 X 3 6 is- [R 32 -R 32 -R 3 1 -R 32 -R 32 -R 33 -R 31 and X 37 is -[R 32 -R 31 -R 32 -R 32 -R 33 -R 3 1 -R 32 wherein R 3 1 is a basic hydrophilic amino *0 acid, R 32 is a hydrophilic, or hydrophobic amino acid, and n is from 2 to The method of claim 2 wherein the peptide includes the following basic 0 25 structure X 4 0 26 R 31 -R 32 -R 3 2 -R 33 -R 34 -R 32 -R 32 -R 31 -R 32 -R 32 -R 32 -R 3 2 -R 3 4 -R 32 -R 32 wherein R 3 1 is a basic hydrophilic amino acid, R 32 is a hydrophobic amino acid, R 33 is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and R 34 is a basic hydrophilic or hydrophobic amino acid.

11. The method of claim 10 wherein the peptide includes the following structure: Y 40 -X 40 wherein X 40 is as hereinabove described in claim 14, and Y 40 is: R 32 or (ii) R 32 -R 32 or (iii) R 34 -R 32 -R 32 or (iv) R 33 -R 34 R 3 2 -R 32 or R 32 -R 33 -R 34 -R 32 -R 32 or (vi) R 3 2 -R 32 -R 3 3 -R 33 -R 34 -R 32 or (vii) R 3 1 -R 32 -R 32 -R 3 3 -R 34 -R 3 2 -R 32

12. The method of claim 10 wherein the peptide includes the following structure: X 40 -Z 40 wherein X 40 is as hereinabove described in claim 10, and Z 40 is: P 3 1 or I l.~lla*rlnll~bs.ara 139 (ii) R 3 1 -R 32 or (iii) R 3 1 -R 32 -R 32 or (iv) R 3 1 -R 32 -R 32 -R 33 or R 31 -R 32 -R 32 -R 33 -R 34 or (vi) R 31 -R 32 -R 32 -R 33 -R 34 -R 32 or (vii) R 31 -R 32 -R 32 -R 33 -R 34 -R 32 -R 32

13. The method of claim 10 wherein the peptide includes the following structure: (Y 4 0)a-X40-(Z40)b, wherein Y 40 and Z 40 are as previously defined in claims 11 and 12, a is 0 or 1, and b is 0 or 1.

14. The method of claim 2 wherein the peptide includes the following basic structure X 50 R 4 1 -R 42 -R 42 -R 41 -R 42 -R 42 -R 4 1 -R 4 1 -R 42 -R 41 -R 4 1 wherein R 4 1 is a hydrophobic amino acid, and R 42 is a basic hydrophilic or neutral hydrophilic amino acid.

15. The method of claim 2 wherein said peptide includes the following basic structure X 52 R 42 -R 41 -R 42 -R 42 -R 4 1 -R 4 1 -R 42 -R 42 -R 41 -R 42 -R 42 wherein R 4 1 is a hydrophobic amino acid, and R 42 is a basic hydrophilic or neutral hydrophilic amino acid.

16. The method of claim 2 wherein the peptide includes the following basic P' structure X 5 4 -R41-R42-R42-R41-R42-R42-R42-R41-R42-R42-R41-R41-R42-R42-R43-, Swherein R41 is a hydrophobic amino acid, R 42 is a basic hydrophilic or neutral V hydrophilic amino acid, and R 43 is a neutral hydrophilic amino acid. i 25 17. The method of claim 2 wherein the peptide includes the following basic structure X 56 -R41-R42-R41-R41-R-R4-R4R41-R41-R42-R42R44-, wherein R41 is a hydrophobic amino acid, R 42 is a basic hydrophilic or neutral hydrophilic amino acid, and R 44 is a neutral C' hydrophilic amino acid or proline. 30 18. The method of claim 2 wherein the peptide includes the following basic structure X 58 -R41-R41-R 42 -R 42 -R 41 -R 42 -R 42 -R 4 1 -R 41 -R 42 -R 42 -R 4 R 43 wherein R41 is a hydrophobic amino acid, R 42 is a basic hydrophilic or neutral hydrophilic amino acid, and R 43 is a neutral hydrophilic amino acid,

19. The method of claim 2 wherein the peptide includes the following basic structure X 60 -R 4 1 -R4 1 -R 4 3 -R 42 -R 4 1 -R 4 1 -R 4 1-R 41- R

41- R -R4 R41-R41-R42R42 1-R42-R42-R42- R41-, wherein R41 is a hydrophobic amino acid, R 42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid. ^*A U I- -~n-rr t~~ The method of claim 2 wherein the peptide has a structure selected from the group consisting of: R41-R4R 4 2 -R 4 1 -R 4 2 -R 42 -R 4 1 (ii) R 41 -R 41 -R 42 -R 42 -R 41 -R 42 -R 42 -R 41 (iii) R 42 -R41-R 4 1-R 4 2 -R 4 2 -R 4 1 -R 4 2 -R 4 2 -R41; (iv) R 42 -R 42 -R 4 1 -R 4 1 -R 4 2 -R 4 2 -R 4 1 -R 4 2 -R 42 -R 4 1 and R4 1 -R42-R4 2 -R4 1 -R4 1 -R 42 -R 4 2-R 4 1-R 4 2 -R 4 1 wherein R41 is a hydrophobic amino acid, and R 42 is a basic hydrcphilic amino acid or a neutral hydrophilic amino acid. 21. The method of Claim 2 wherein said peptide is melittin. 22. The method of Claim 2 wherein said peptide is an apidaecin. 23. The method of Claim 2 wherein said peptide or protein is a defensin. 24. The method of Claim 2 wherein said peptide or protein is major basic protein of eosinophils. 25. The method of Claim 2 wherein said peptide or protein is bacterial permeability-increasing protein, 26. The method of Claim 2 wherein said peptide or protein is perforin. 27. The method of Claim 1 wherein the peptide has the following structural formula: -(Lys Ile Ala Lys Lys Ile Ala)n-, wherein n is from 2 to 28. The method of Claim 1 wherein the peptide has the following structural formula: -(Lys Phe Ala Lys Lys Phe Ala)n-, wherein n is from 2 to 29. The method of Claim 1 wherein the peptide has the following structural 25 formula: *i -(Lys Phe Ala Lys Lys Ile Ala)n-, wherein n is from 2 to The method of any one of the preceding claims wherein said composition further comprises an ion having pharmacological properties. 0 a 31. The method of Claim 30 wherein said ion having pharmacological properties I 3o is a fluoride ion. 32. The method of any one of the preceding claims wherein said composition further comprises chlorhexidine. 33. The method of any one of the preceding claims wherein said composition further comprises sanguinarine HC1. Dated 3 October, 1995 Magainin Pharmaceuticals, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON S /T 01N:\LIBAAIO0288:JJN