AU735298B2 - Hydrophilic signal oligopeptides and methods of therapeutic use - Google Patents
Hydrophilic signal oligopeptides and methods of therapeutic use Download PDFInfo
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- AU735298B2 AU735298B2 AU81834/98A AU8183498A AU735298B2 AU 735298 B2 AU735298 B2 AU 735298B2 AU 81834/98 A AU81834/98 A AU 81834/98A AU 8183498 A AU8183498 A AU 8183498A AU 735298 B2 AU735298 B2 AU 735298B2
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
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Description
Our Ref: 697244 P/00/011 Regulation 3:2
AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Address for Service: Invention Title: Matthias Rath 880 Bear Gulch Road Woodside California 94062 UNITED STATES OF AMERICA DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Hydrophilic signal oligopeptides and methods of therapeutic use The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 [VL96 ON XM/XLI 60:11 IJA TO, 0/ITT METHOD OF PRODUCING VACCINES FROM PROTOIN SIGNAL OLIGOPEPTIDES Field The present invention relates to methods of producing therapeutic peptides an~d peptides produced thereby.
The discovery of the genetic code by Wabso and Crick four decs ago defined 9:9. the principles by which genes (the gee code) encode for proteins by determining the sequence of amino- acids. As is known, proteins are important carrers of metabolic information in living organisms. Exogenous protein organisms such as the MIV virus, ad. othnd r endogenous; protins suc as -ba whc aueIiaee, r ls h m of miany human-diseases.
The genitic code deties the Structure of proteins, thereby dictating the fiUction Of the pMotin In the vast majority of proteins, biological activity and the specific function of the Protein is primarily mediated via specific amino acid sequences locaed on dhe outside surface of the three dimensional rot- 1m protein code determines the relation between structure and function within a Protein sequenice and, thereby effects a specific biological action. Therefore, the protein code is the biological language for protein-mediat.ej informsation tnsfer dining health and disease. The interaction of hormones and other ligands with their respective 99*99 rcepors of enzymes, with'protein susrates, of adhesive proteins with integrins, and of antibodies with antigens, as well as other protein actions and interactions are determined by the same structureffimetion principles and the same biological language. The protein code also provides a missing link in the regulation of protein synthesis. Proteins also have important feed-back functions diretly or indirectly modulating the synthesis rate of tha PrT0ein- The Structire/fietion relation of proteins, which determines protein actions and interactions, are hereafter referred to as the protein code.
Conventional drug therapy is fiequently compromised by an unknown therapeutic Elechanisut and by a wide zange of side effect arid considerabletoxicity. Conventional gene therapy uses some of the protein interaction principles mentioned above to increas the therapeutic specificity of the Pharmaceutical and the delivery of the drug to the target cells and organs, which results in a reduction in toxicity and safty compared to conventional drug therapy. However, gene therapy has its disadvantages as it requires that the specific sequence of the entire disease causing protein be determinecL That is, in order to treat or fight a disease, scientists attempt to detemine the genetic code by replicating the entire amnino acid sequence of the disease causing protein. Gene therapy is 1:-AV, LE LLYz 8V5 z 9+ 9 A 9 D U 0 S I I 1 0 D S 9 1 A 9 0 N V 0 I L L 0 L t [IVL96 ON YI/X~L] 60:11 INA 10, SO/TT compromised by its technological requirements and its high cost. The development of gene therapy drugs is a time consuming process through the research and development phase of the drug. the clinical studies phase, as well as in the drug mnacrig and therapy phase of the drugs so developed. For example, in gene therapy, identification oft the target disease: causing protecins spans anywhere from months to years. The productiton of a drug, in-vitro tests, in-vivo tests alone takes approximiately another several years.
First cincal studies span between 5 to 10 years. This causes drugs developed through gene therpy to be very expensive, and restricts its therapeutic application to only certainmore profitable and exclusive areas of diseases in the foreseeable future.
Thczefaru there is a need for a method of therapy that allows for the itreto of pathological interactions with maximum, effective==s.
There is*a further need for a method of therapy that ealsmaximum terpewic Yetanoherneed is for a method of therapy that is safe and eliminates or limit toxicity, and allows for controlling undesired biological side-iffects by optimizing the length and eoiiposition of the therapeutic peptide.
There is also a need for a therapy method that reduced the time and expense of development of therapeutic peptides, to a fraction of conventional gene therpeutic research and development. Most imnportantly, there is a need for a targeted and safe therapy method which will allow clinical application of drugs for a variety of disease causing proteins that have been ignored because of the cost of development *see.
6:400:Just as the human language allows for communication and interaction among humans, the protein code is the underlying communication means for the interaction of antigens with antibodies, enzymes with substrates, receptors with ligands, adhesion molecules with integrins and other forms of protein communication. Humans commnunicate. through sentences. Sentences amp in turn composed of words and words are in turn made of letters. Similarly, the three dimentional'structurt of proteins can be analogized to sentences through which protein commiunication takes place. The peptide sequnce of the protein can be analogized to words in the sentence, and the individual aIn acids of the protein can be analogized to letters in words. However, what today remains a mystery in the language of communication in proteins arm the "verbs" of the protein, code sentences.
The description discloses a method of producing therapeutic peptides as vaccines in the. prevention of human disease which are caused by one or more proteins. This methd ofpp3d therapy, in contrast to gene therapy, comprises: a) identifyig the protein responsible for causing the human disease; b) identifying one or more signal 2 E a Z L 9 Z 8 V Z 6 Z 9 U 0 Ia I LY 0V~ D pR U IO S aI9 aA V 0 t 9- t IVL96 ON YH/XJA [i~~geONYH/1] 6:11 IMA TO, Go/TT oligopepcie Sequences within the sttucwf of the discase causing proein, te one or more signa oligopepds rePresating t amino Acid seuam of mximum hydrophilicity and/or maximum surface probability, and/or maximum electrical charge of the protein; and c) synthesizing one or more vaccine oliggpeptides, the vaccine oligopeptides having amino acid sequences corresponding to the amino acid sequences of the signal oligopeptides identified in b) Preferably, the method further comprises an evolutionary comparison step, wherein one or more species of animals in an evolutionary chain are selected to produce different vaccine oligopeptides to the same disease causing protein.
The method preferably further comprising an optimization step, wherein the one or more vaccine oligopeptides are manipulated through one or more amino acid residue 0*0: substitutions, amino acid deletions, or amino acid insertions, or any combination thereof, to produce an optimized immunogenic response in vaccinated humans.
Prftambly* the nzeth of the invention coms a method Wherein anog ~~esp ronse of doe vaccine oligopu"p'Ytid in hwunisehx byeetin of ie vaccic oliguppie to form a linr polypeptd&.
Also, preferably, the method of-th invention comprises a meth~od wherein di iunnmnancrespoms of die vaccieciaerd in hunmn is enhanceed by repetition of dhe vacciune oigo-peptides. to form a cyclic polypepre.
In yet anotcr preferre im the inetd of fe invention comprisesa medhod wherein the imuoei epneof the vacine ofigoa;P;ptd 4s in bmumus is aa~ehanceed by coupling of out or more Qf the vaccuie oAWigopeptide to animnoei pmien ml UDT-nlltciflh Preferably, the'amnino acid sequence of maximum hydrophilicity, or maximum surface probability or maximumi electrical charge is identified by a hydrophilicity determrining algorithm, a surface probability determining algorithm or an electrical charge determining algorithm, respectively.
Advuntares ofPjtd heuwoe ene Mmmoyv and Dm eMuv PePtide therapy may open a new field of therapeutic options in medicine. For the first time, ft nay be possible to develop specifc therapeutic agents, which target only Che LU 3 IE Z L Z V B 9+
L
IVL96 ON YH/YJl N N/XL]60:11 HMd TO, GO/TT affected organ or cell system, without any side effects. A particular preferred advantage may be the fast identification of the therapeutic peptides, its short development phase and the resultant low cost. Furthermore, this new therapeutic technology may allow for the control of many diseases that are currently untreatable.
The bencfits of peptide therapy become~mogc obvious especially when compared to gene therapy. Giene therapy requires thei first a gene specific for a given diseas be identifiedL Once identified, then the process require that it be artificially reproduced and..
then it be reintroduced into the patient' s body. This procedure is both time consuming and its outcome is ine- riale. Thus, the therapeutic efficacy of gene therapy. canonly be achieved after Years of research and development and utmnt, if at all.
Ina conitast, peptide therapy is based on the principle that at some point, the 0 genetic code must be translated into proteins that then interact with cells, and that health or disease is ultimately decided at the level of proteins- The identification and therapautic, use of the key oligopeptides within a selected protein is the most direct, specific, effeicve, as well as the safest and most affordable way for the prevention or treatinert of the disease. 4Compared to genec therapy, the application of peptide thierapy' may shorten the time for .dvelopment: and treatment for many human dispases. Thereforepeptide therapy as dcsefibed below has the following advantages.
Peptide therapy is a highly effective form of treatment The discovery of the ~peptd code provides the rationale for deciphering the comncton code of proteins in health and disease. This discovery may be 'used therapeutically to intercept pathological mtleraetions of human disease with maximum effectiveness.
0 0 Peptide therapy may also enable maximumi therapeutic specificity. Based on the geaprMMs wduiwdn of the strucrurv/ffimction relation of specific protein signals, peptide therapy may allow therapeutic targeting with unprecedented specificity.
Furthermore, peptide therapy is catunely safe. The use of synthetic analogs to physiologic compounds essentially eliminate the problem of toxicity. Possible undesired biological side-effects may be controlled by optimizing the length and composition of the theapeticpeptide.
Time and expenses for the development of therapeutic peptides is a fraction of conventional therapeutic research and development Identification of potential therapeutic PePtides takes minutes; in vitro screening of potential peptides is* a matter of weeks; animal Studies should provide first in vivo results within a few monthis. Most importantly, the specificity anid safety backgroundf of peptide theripy should allow clinical snties without delay.
The advantages of peptide therapy become even more obvious when this novel therapeutic approach is comparWed, to conventional therapies- Conventional drug therapy is frqently comnpromi~sed by an unknown therapeutic mechanism and by a wide range of 4 LE /ZZ L19Z 8VZB Z Lq+: a A 2 D U 0 5 1 1 1 0 j 3 a I A e a !IN V 0 L L L 0 S L L side effects and considerable toxicity. Gene therapy is compromised by limited availability, its technological requirements and its high costs, which restricts its therapeutic application to exclusive areas in the foreseeable future. Heterologous or synthetic antibody therapy, the therapeutic application of antibodies produced outside of t the patient's body, can cause incalculable adverse reactions by the patient's immune system against these 'foreign' antibodies. In contrast, peptide therapy makes elegant use of the patient's own immune system thereby excluding adverse immunological reactions.
Brief Description of Tables and Figures Table 1; shows the various amino acids found in proteins and their hydrophilicity and surface probability values.
Fig.lA and 1B show several of the protein code interaction principles including legibility, accessibility, variability, and specificity. Fig. 1C shows the oppositely charged amino acids can attract each other thereby enhancing confirmational specificity. Figure 1D shows vaccines stimulating the production of antibodies which block pathological communication pathways not only in the prevention and treatment of infectious diseases but also in the therapy of neoplastic diseases, metabolic disorders and other diseases.
Fig. 2 shows the method of this invention used in peptide therapy in diabetes. This figure shows the three hydrophilicity peaks in the glucagon precursor sequence Fig. 3 shows Peptide therapy in HIV infections. Synthetic analogs to signal oligopeptides of the HIV envelope protein GP 160 or the cell receptor CD4 are used as vaccines. The hvdrophvlicity blot revealing potential signal oligopeptide sequences of GP 160 is shown in the upper part of figure 3.
Fig. 4 shows the method of this invention used in Direct Peptide Interception Therapy (Direct PIT).
Fig. 5 shows the method of this invention used in Indirect Peptide Interception Therapy (Indirect PIT) and optimization of the therapeutic peptide size or sequence by amino acid residue substitution, deletion and/or insertions.
SFig. 6 shows the method of this invention used in Peptide Regulation Therapy (PRT) including the methods for identification, design, development and therapeutic use of synthetic analogs to signal oligopeptides as negative feed-back regulators for the S' synthesis rate of selected proteins.
Fig. 7 shows the method of the present invention used in the development of In-Vitro Diagnostic Assays.
Fig. 8 shows the method of the present invention as described in Example No. 1.
Detailed Description Infectious diseases, cancer, cardiovascular and other human diseases develop by means of one or more pathogenicity-mediating proteins, or disease causing proteins.
S: Blocking the action of these proteins allows the specific therapeutic interception of a pathological communication, thereby blocking disease propagation.
In the human language eliminating or changing the verb of a sentence renders the whole sentence meaningless. Similarly, blocking the protein code verbs (signal oligopeptide sequences) can be therapeutically used to block the undesired action or k interaction of an entire protein. If the verb in any sentence is altered, i.e. change eating to walking, the entire meaning of the sentence changes, or the sentence is rendered unintelligible. These verbs of the protein code, referred to as signal oligopeptides, determine the very specific function of a protein. Similarly, if a signal oligopeptide is altered (or blocked) in any given protein, either that protein's function changes, or the protein is rendered function-less. Interference with signal oligopeptides, these verbs of the protein code sentences, can lead to substantial modification or loss of the biological message of a protein. This modification or loss of the biological message of the protein can be used in peptide therapy to the advantage of a patient.
The specific action of these oligopeptides is determined by a characteristic combination of shape and electrical charge (both anionic and cationic) within the same signal sequence. Protein information transfer and protein interaction is dependent on the accessibility of the signal oligopeptide sequence. Therefore, in the majority of proteins, the sequence signals are localized on the surface of the protein. Signal oligopeptides are enriched with charged amino acids such as cationic amino acid residues arginine and lysine and/or the anionic amino acid residues glutamate and aspartate. Sometimes, these signal oligopeptides are in a versatile arrangement with neutral spacer amino acids.
Therefore, signal oligopeptide sequences are generally represented by the regions of maximum hydrophilicity on the surface of the protein molecule.
A new type of signal is represented by oligopeptides which obtain their characteristic conformation or shape by a specific arrangement of oppositely charged amino acid residues within this oligopeptide sequence. These residues with opposite charge can attract each other thereby modulating a characteristic folding of this signal sequence. For example, in the signal sequence RGD the cationic residue arginine and the Sanionic residue aspartate attract each other leading to a characteristic folding of this tripeptide around the 'spacer' residue glycirie.
The specific metabolic function of a protein is dependent on the specificity of its biological signal oligopeptide. The signal character of a specific signal oligopeptide is determined by a characteristic combination of electrical charge with structural conformation. Within a protein, RGD and analogous tripeptides can serve as strong primary anchors while the specific biological message is mediated by additional longer :and more complex signal oligopeptides.
Synthetic analogs of signal oligopeptide sequences are used therapeutically in several ways. First, synthetic analogs of signal oligopeptide sequences can be used as competitive inhibitors of pathological communication. Second, synthetic analogs of signal oligopeptides can be used as vaccines. This second therapeutic approach makes use of the fact that signal oligopeptides on the surface of the protein are identical with the antigenicity determining epitopes of this protein. Thus, antibodies are interceptors of metabolic communication. Binding the signal oligopeptide sequence of a protein to antibodies and other mediators of immune response reduces or blocks its metabolic interaction. If synthetic analogs to signal oligopeptides are used as vaccines it is necessary to render these peptides antigenic and to allow their discrimination as 'non-self.
Synthetic analogs to signal oligopeptides can be rendered immunogenic by coupling them to haptens or by other conventional methods.
The method of this invention using synthetic analogs is based on the discovery of the primary structural principles determining immunogenicity. The discrimination between self and non-self between species of animals and humans is primarily based on amino acid residue substitutions or other residue variations within the signal oligopeptide sequences of a protein. By making use of this discovery effective therapeutic signal oligopeptides can be rapidly produced in the following way: signal oligopeptides of a given protein in one species of animals are the antigenicity determinants of this protein in another species of animals. To block the action of a pathogenicity-mediating or disease causing protein in the treatment of a human disease the synthetic signal oligopeptide vaccines are designed by copying corresponding amino acid signal sequences from another species. A glucagon signal oligopeptide vaccine for the treatment of diabetic patients would-be based on glucagon signal sequences from rabbits, sheep, mice or other species. A titration of the therapeutic efficiency is possible using the evolutionary chain method described below. The greater the genetic and evolutionary distance of the selected animal species to humans the greater its antigenicity and, consequently, the greater its therapeutic efficiency as a vaccine.
Furthermore, signal oligopeptides of a protein are identical with the potential antigenic determinants. Antibodies and other mediators of immune response are interceptors of specific biological communication. Signal oligopeptides as promoters of differentiated protein communication and immune response mediators as interceptors form sophisticated network of biological communication. Therefore, decoding the physiologic aspects of this communication network will lead to a precise understanding of millions of metabolic interactions including the principles for development and differentiation of the body, which will lead to the therapeutic control of many diseases and eventually their eradication as causes of human mortality.
Turning now to the figures the invention is described in detail. Figures 1 A and 1B show principles upon which the protein code functions. Within the amino acid -sequence of a disease cause protein one or more signal oligopeptides represent the "verbs" of the protein code which determine the specific action and interaction of that protein. This is referred to as the legibility of the protein. The signal oligopeptides of a protein are enriched in electrically charged amino acids (either cationic or anionic) and represent a segment of maximum hydrophylicity within the protein sequence. An infinite number of possible combinations between amino acids with different charges as well as neutral residues provide the variability for differentiated metabolic communication. The specificity of a signal sequence is the result of a characteristic combination of charge distribution and structural conformation within the signal oligopeptide sequence. Figure 1B shows the oppositely charged amino acids attracting each other thereby enhancing conformational specificity. Signal oligopeptides mediate specific information transfer to their metabolic counterparts. Substitution, deletion or other amino acid residue I variations within the signal sequence of a protein enable differentiation between 'self and 'non-self. Signal sequences are the antigenic epitopes of a protein and are responsible for potential immune responses when exposed to other organisms. Direct and indirect Peptide Interception Therapy (PIT) can be used to intercept undesired or pathological communication and thereby block the disease. Figure 1C shows direct PIT synthetic analogs of signal oligopeptides used to competitively inhibit the interaction of proteins.
Indirect PIT makes use of synthetic oligopeptides rendered immunogenic. Figure ID shows vaccines stimulating the production of antibodies which block pathological communication pathways not only in the prevention and treatment of infectious diseases but also in the therapy of neoplastic diseases, metabolic disorders and other diseases.
Peptide Interception Therapy (PIT) The metabolic interaction of proteins is primarily modulated by one or more oligopeptide signal sequences which determine the metabolic interaction of a protein.
Peptide Intercepition Therapy (PIT) is defined as the specific therapeutic interception of pathological or undesired protein actions and interactions by the therapeutic use of synthetic analogs to the signal oligopeptide sequences of this protein. To intercept the undesirable action of the disease causing protein, only the signal oligopeptide (protein verb) of the disease causing protein is therapeutically blocked.
First, using conventional methods, a disease causing protein, such as Glucogon, which mediates diabetes, is identified. These signal oligopeptide sequences are located on the surface of the disease causing protein and are represented by one or more sequences of maximum hydrophilicity region hydrophilic maxima) or maximum electrical charge within the amino acid sequence of the protein. The signal oligopeptide sequences of this protein is identified from its primary structure by use of a protein data base in combination with a suitable algorithm, such as hydrophilicity or surface probability algorithms. Examples of hydrophilicity and surface probability algorithms are shown in Table 1. In this algorithm the highest hydrophilicity or probability values have to be assigned to the charged amino acids lysine, arginine, aspartate and glutamate followed by asparagine and glutamine.
b Synthetic analogs to signal oligopeptide sequences can be therapeutically used to block the pathological effects of the disease causing protein. An unlimited number of signal oligopeptide analogs can be synthesized covering the entire sequence of a selected hydrophylicity peak or parts of it.
a 4 Table 1 Table 1: The Maxima of the Following Algorithms -or Modifications Thereof- Can Be Used to Determine Potential Signal Ol1gop~pttdes In the Primary Structure of a Protein From a Protein Sequence Database Amino Acid A. Hydrophyticity B. Surface Probablity Residue Algorithm Algorithm"* Aspartate Glutamate Lysine Aspartate or A Glutamate or G Serine Asparagine Glut amine Glycine Praline Threonine Alanlne Histidlne Cyste ine Methionine Valine Isoleucine Leucine Ty ros inte Plhen yia an in a Tryptophan sparagine ~lutamine 3.'0 3.0 3.0 1.6 1.6 0.3 0.2 0.2 0.0 0.0 -0.4 -0.5 -1.0 -1.3 -1.5 -2.3 -2.5 -3.4 9.S 8.1 8.4 9.7 8.4 7.8 8.4 4.8 4.9 6.6 2.6 4.8 3.6 3.4 7.6 4.2 5.1
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C. Algorithm Based on the Following Amino Acid Categories: I. I ighest Values Assigned to Charged Amino Acids: Aspartate. Glutamate. Lysine, Arginine, Histidine 2. Medium Values Assigned to Uncharged Polar Amino Acids: Asparaglne, Glutamine, Glycine, Cysteine. Serine, Threonine, Tyrosine 3. Lowest Values Assigned to Non Polar Amino Acids: Alanine, Vailne, Leucin. isoleucine, Praline, Phenylalani no, Methionine, Tryptophan According to Iiopp TP. Woods, KR. 1981. Proc. Natl. Acad. Scd. USA; 78: 3824- 3826.
Bcger. Proceedings of the 1988 Mami Blolrechnology Winter Symposium. 10 Oxford and Washington. IRL Press.
Signal tetrapeptides, pentapeptides, hexapeptides and longer peptides represent primary candidates for specific peptide therapy. Shorter peptides, such as the tripeptide RGD, are less specific and ubiquitous side effects limit their broad therapeutic use.
k Figure 2 shows the fundamentals of Peptide Interception Therapy (PIT). Proteins are essential carriers of specific metabolic information. Moreover, proteins are frequently mobile which makes them ideal and versatile communication molecules. This figure illustrates several key elements of direct PIT in peptide therapy. In conventional gene therapy, the entire three dimensional protein structure (protein sentence) is required to counter the effects of the disease causing protein. However, in direct peptide intercept therapy, only the signal oligopeptide sequence ("verb") has to be blocked. Figure 2 also shows methods for identification, design, development and therapeutic use of synthetic analogs to signal oligopeptides in Peptide Interception Therapy as direct competitive inhibitors of selected protein actions.
As further described in detail below, peptide Interception Therapy (PIT) is used in two principal ways: direct PIT, which uses synthetic analogs of signal oligopeptides as competitive inhibitors of pathological or undesired metabolic interaction; and indirect PIT, which uses synthetic analogs as vaccines to stimulate the production of specific antibodies. In Indirect PIT, antibodies developed from vaccines, not the therapeutic peptide itself, function as interceptors of protein communication.
Use of Signal Oligopeptide Sequences in Direct Peptide Interception Therapy
(DPIT)
As indicated above, Direct Peptide Interception Therapy (Direct PIT) uses synthetic analogs of signal oligopeptides as direct competitive inhibitors for undesired protein communication. Direct blocking of pathogenicity mediating protein communication leads to the control of the related disease or clinical condition. This therapeutic approach is preferentially used in acute conditions, e.g. antithrombotic or fibrinolytic therapy. Direct PIT is preferentially used intravenously in higher therapeutic dosages of the synthetic peptide. Poly-oligopeptide analogs, time release delivery systems and other modifications of the peptide delivery mechanism are used to extend the range of various therapeutic applications.
Figure 2 demonstrates a method of peptide therapy in diabetes and the signal sequences of proglucagon and therapeutic alternatives for peptide therapy in diabetic patients. Conventional treatment in diabetes focuses on increased availability of insulin.
Peptide therapy enables an alternative approach. Synthetic analogs to the signal sequences of glucagon can be therapeutically used to attenuate the effect of this insulin antagonist. Note the three hydrophilicity peaks in the glucagon precursor sequence B, The mature glucagon hormone is activated by contact and charge redistribution within peaks A and C. PIT therapy could have two distinct targets. First, blocking charge redistribution of precursor molecule (PIT for Peak A or C) prevents activation of the precursor to mature hormone. PIT targeting peak B prevents the action of the glucagon [t7L96 ON XH/Y~L] 60:TT 184 TO, SO/TT hormone. Second, vaccination with synthetic glucagon signal oligopeptides rendered immunogenic by the described methods in this disclosure, or other suitable methods blown in the art, is a baseline treatment fbr diabetic patients.
Figure 4 shows the steps taken'in order to use the are of axmum hydrophilicity of the protein sequence (signal oligopeptide) to develop synthetic analogs to the signal oligopeptide for use as competitive inhibitors.
Use of Signal Oliffopiptide seauences in Indirect Pepfide Intrcept Tberapy Today vaccines arm essentially limited to pxuphylactics and therapy of infectious diseases. Heterologous; or synthetic antibody them"p, the therapeutic application of Antibodies produced outside of the patient's body, can cause incalculable adverse reactions by the patient's immune systern against these 'fore' antibodies.
Peptide therapy using indirect PIT enables the extnion of the preventive and therapeutic use of vaccines to all areas of medicine. The great advantage of oligopeptide vaccies as compared to conventional vaccines, is that the entire protein is not used as a vaccine. Only 3Ynthetic analogs to one or more of the signal oligopeptides of the selected protein ame used to produce the vaccine. Peptide therapy by targeting the signal ohgopeptide sequence "verbs" of the disease cawsing protein, makes elegant use of the patimes own imimune system thereby excluding advems immunological reactions.
Indirect PIT is implemented in the following manner. Signal oligopeptides of a given protein in one species of animzals are the antigenic: epitopes of this protein for The muuesystem of another species- To block the action of a pathogenicity-medjan protein in the treatment of a human disease, the amino acid residue sequence of the oligopeptide vaccines should be homologous to the signial sequences of the same protein but from another species of animals. Thus, a glucagon signa oligopeptide vaccine for the ftiearent of diabetic patients would be based an the glucagon-signal scquxaces from rabbits, sheep, umice or other species. The aim of this residue manipulation is to create an matigenic epitope without compromising the ability of the antibodies produced to cffectively block the metabolic interaction of the proteini. This therapeutic approach mimics nature's way to discriminate between 'self and 'non-seLf and make therapeutic use of it-.
Indirect PIT is based on the therapeutic use of antibodies produced by the patient's own immune system against the signal oligopeptide: sequences of proteins mediating pathogenicity for undesired metabolic action. Indirect PIT is preferecntially used for preVentive therapy for the treatment of chronic conditions or as adjuncts to direct PIT or other forms of acute therapy- Figure 3 shows peptide therapy in 19V infeczions. First the IV envelope protein GP 160 or the cell receptor CD4 is identified- The area of maxiumi electrical charge of I E E z 19 z 8 V z 6 z 19 9 A~ 9 OSIIIO O1APC !N OI;I !1 the HIV envelope protein is then determined using the hydrophylicity blot which reveals potential signal sequences of GP 160 is used to identify the areas of maximum hydrophilicity and maximum electrical charge. Synthetic analogs to signal oligopeptides of the HIV envelope protein GP 160 or the cell receptor CD4 are then used as vaccines. k The specific .antibodies produced effectively inhibit the infection of cells. Other targets of HIV peptide therapy are the regulator proteins Rev and Tat with the aim to block viral replication.
Figure 5 shows the principles of Indirect Peptide Interception Therapy (Indirect PIT) including the methods for identification, design, development and therapeutic use of synthetic analogs to signal oligopeptides in Peptide Interception Therapy as vaccines to stimulate a specific immune response with the aim to decrease or block selected protein actions.
Enhancement of Immunogenic Response in Indirect Peptide Therapy The protein code is a key for individual development within a species as well as for the evolutionary diversification of species. The effectiveness of signal oligopeptides to mediate specific biological messages were the ultimate criterion for the evolutionary advantage of a protein and, thus, for the evolutionary survival of the gene encoding for it.
Genetic mutations leading to the substitution of one or more amino acid residues within a signal oligopeptide sequence were an economic and therefore frequent mechanism to modulate and differentiate protein action and thereby promoting evolutionary diversification.
The signal oligopeptides of a given protein are identical with its potential antigenicity determining regions (antigenic epitopes). Furthermore, the primary mechanism determining antigenicity between different individuals and different species are amino acid residue substitutions, omissions and other residue variations within the signal oligopeptide sequence(s) of a protein.
a As shown in Figure 5, the designer of therapeutic compounds for indirect PIT makes use of the evolutionary chain. The further apart two species of animals are in the evolutionary chain, the more amino acid residue mutations occurred, including mutations in the signal oligopeptide sequences. Therefore, the further an animal species is from humans in the evolutionary chain, the more antigenic is the therapeutic peptide derived from that animal. A titration of the therapeutic efficiency of indirect PIT is possible.
S: Indirect PIT therapy with synthetic analogs to glucagon signal oligopeptides from a fish species is more effective than those from a mammalian species in blocking human S- glucagon action.
Therefore, an evolutionary comparison method is used, wherein one or more Sspecies of animals in an evolutionary chain are selected to produce different vaccine oligopeptides to the same disease causing protein. It is desired that each vaccine oligopeptide from the different species of animals produce a different immunogenic [t7L96 ON XH/XJL] WI:T I il TO, GO/T response in vaccinated humans. 1Thereafter, te vaccine oligopeptide that produced the dlesired u uogicresponse in humans is selected for use in hunzaxs.
The protein code provides the basis for the immunological differentiation betwee* humans and animal species. Substitutions, omissions, and other variations of one or more amino acid residues within the signal sequence of the protein enable an organism to differetiate between 'self and 'non-self. Thus. the prtin code comprises the basitc lagaeof imimunology.
Antigenicity required for effective indiret PIT therapy can also be stimulatd in conventional ways, e.g. by omitting one or more amino acid residues at the N-termninal end of any given sequence (start of sequence), by omaitting one or more amnino acid res at the Ctniaedofnygiven sequence (end of terminal), by omitting one sequence, by substitn one or more of the aioacid residues within any given sequence without consideration of charge and polarity of the substitution residue, by substituftin one or more of the ami; acid residues within any grwen sequI~gces with anm acid residues with smilar chaog and/or polarity, by omitting one or more am acid residues within any: given sequencr4 by coupling the therapeutic peptides to defined haptesas or othel i ungenic compounds -enhancing 'nan-self recognitioni, or a combination of two or moire of the mntioned methods.
~Use 9_1Shmial 01iroDeM tide Seauzees irn tinde rngulatn Thmrawy (PKf A third therapeutic maechanism using synthetic analogs of signal oligopeptides is as feedback regulators for protein syndmeis. Peptide Regulation Therapy (PRT) madkes therapeutic use of synthetic analogs of signal oligopeptide sequenees to decrease the synthesis rate of an undesired protein via feedback mechanisms. The synthesis rate of itayproteins is determined by the amount of protein end-product available. The signal sequences of pathogenicity mediating proteins ca be used to decrease the "ythesis of this protein via direct or indirect feedback mechanisms.
Figure 6 shows the method of Peptide Regulation Therapy (PRT) including the methods for identification, design, developmcnt and therapeutc use of synthetic analogs to signal oligopeptides in Peptide Rxgulation Theray as negafmv feedback regulators for the synthesis rawe of selected protew&s Again, the amc of maximum hydrophilicity of the protein sequence is determined using one of the following methods; hydrophilicity algorithm such as that described by Ilopps, Surface probability algorithm, any algorithm which assigns values to amino acid residues, high=r charged amino acids receiving gretcr value over uncharged polar amino acid residues, over non-polar amino acids, or any combination of the above-mentioned iliethiods.
Once the protein sequence's oligopeptide is identified, synthetic analogs are A p rodce to match the sequence of the oligopeptide. If the synthetic analogs are. not 13 IE /tz t[gz BVES z Lg+! @Ag /OS 110 S8LL9jN tt~ [0-9 effective as feedback regulators, the-analogs are optimized to produce the desired effect using peptide size alteration by amino acid residue substitution, deletion, insertion, or any combination thereof.
Use of Signal OligoDeptide Sequences for Development of in vitro Diagnostics Kits Polyclonal or monoclonal antibodies for a protein can be manufactured by first identifying the antigen. Synthetic analogs to one or more signal sequences of a proteins are used as antigens. These signal sequences are determined from a data base by making use of algorithms for hydrophylicity or surface probability. For clinical diagnostics the signal sequence of the protein should preferentially be chosen from a database of human proteins.
To optimize specificity of the antigen the signal oligopeptide should be at least a tetrapeptide or preferentially longer oligopeptides. Polyclonal or monoclonal antibodies are then raised according to established methods using adjuvants or other haptens. The same synthetic signal oligopeptide analogs used as antigens can be used to test the specificity of the antibodies. Figure 7 shows the steps involved in the method of using Signal Oligopeptides sequences in in-vitro diagnostic assays.
Use of Signal Oligopeptide Sequences in Therapeutic Applications of Peptide Therapy Infectious diseases. The most immediate application of peptide therapy is the prevention and treatment of infectious diseases. Every stage of any type of infectious disease is controlled by proteins which mediate adhesion, invasion and other mechanisms of pathogenicity. Effective therapeutic interception of biological signals within these pathogenicity-mediating proteins must lead to the control of the infection itself. As discussed above, for diseases mediated by xenologous proteins (infectious diseases) a signal sequence is chosen from xenologous protein (toxin) as basis for the vaccine in humans. The vaccines are then used for the prevention and treatment of the infectious disease.
Neoplastic Diseases. Another area with immediate applications for peptide therapy is the treatment of neoplastic diseases. Invasive growth and metastatic spread of any type of cancer is mediated by certain proteins and their signal sequences. Synthetic analogs to the signal sequences of these proteins should be developed as an effective therapy for different forms of cancer in their early stage as well as their S invasive and metastatic stages.
Metabolic disorders. A novel therapeutic area for peptide therapy is the treatment S. of metabolic disorders. The potential of peptide therapy is exemplified here for the i treatment of diabetes and hypertension, which are described in detail in the Examples below.
1. Therefore; synthetic analogs to human signal oligopeptide sequences are used for;
I
a. as therapeutic agents for direct competitive inhibition of selected protein interaction, b. as therapeutic agents in feedback regulation with aim to decrease the synthesis rate of the selected protein, c. as therapeutic agents in combination with haptens or other conventional immunogensor adjuvents as vaccines stimulating a specific immune response which blocks or decreases the action of the selected protein, and d. as antigens to produce antibodies against the selected human protein for invitro diagnostic purposes.
2. Synthetic analogs to protein signal sequences from other species are used; a. as therapeutic agents (vaccines) in the prevention and treatment of human diseases, stimulating a specific immune response which blocks or decreases the action of the selected protein in the human body.
b. As therapeutic agents according to sections la and Ib above in the treatment of diseases in the respective animal species.
c. As antigens to produce antibodies against the selected protein for in vitro diagnostic purposes in the respective animal species.
Using the method of the invention as described above aids in the identification of potential therapeutic peptides in minutes; in vitro screening of potential peptides is a matter of weeks; and animal studies should provide first in vivo results within a few months.
Example No. 1 o .Conventional diabetic therapy aims at an increased availability of insulin. Peptide therapy allows a novel and alternative approach by inhibiting the action of glucagon, the insulin antagonist. Amino acid sequence selection and therapeutic design of peptide •vaccines for Indirect Peptide Interception Therapy, exemplified for the development of glucagon vaccines in clinical therapy of diabetes mellitus is described here.
The inhibition of glucagon is accomplished by using the therapeutic peptides analogous to the glucagon signal sequence for direct competitive inhibition or as a 9: vaccine (Figure 2 and First, the signal oligopeptide is identified from a human Glucagon Precursor sequence. Using the available data for Glucagon Precursor sequences in different species, a corresponding signal oligopeptide is identified to the human oligopeptide. Using the evolutionary tree, the relative distance of the available Glucagon Sequence to the human sequence is determined. The evolutionary distance is positively correlated with degree of amino acid variation and therefore, with the antigenicity of the selected protein.
14a The therapeutic peptide sequence is selected among the corresponding sequences according to the following criteria. If a moderate therapeutic immune response is desired, then the therapeutic signal sequence is preferably derived from species that are genetically close to humans mammals). Amino acid residue variation within the therapeutic peptide (vaccine) is sufficient to cause immune response in humans. If a strong therapeutic response is desired, then the therapeutic peptides are designed from species that are genetically more distant to humans Fish, Yeast). The more distant the species from humans, the more amino acid residue variation within the signal sequence, the greater the anitgenicity of therapeutic peptide, and the higher the therapeutic efficiency.
Example No. 2 The specific sequences described in this application as Sequence ID Nos. 1- 360 were selected using the method of the invention in order to provide specific treatments for common human diseases. The sequences so described are the signal oligopeptides characterized by a region of maximum hydrophilicity within the key protein known to mediate the indicated diseases.
For the prevention and treatment of atherosclerosis and cardioascular diseases, Therapeutic peptides from Apolipoprotein(a) (Sequence ID No.s 288 to 295). These peptides prevent the attachment of the most pathogenic lipoprotein fraction inside the artery walls, thereby preventing the formation of atherosclerotic plaques and cardiovascular diseases. Therapeutic peptides from apolioprotein(a) also competitivley detach lipoprotein(a) molecules from their binding sites inside the artery wall deposits, release them from the artery plaques and lead to the natural reversal of athereosclerosis and cardiovascular disease.
The therapeutic effect is achieved by direct application of the peptides as well as by using these peptides as vaccines and having the resulting antibodies block the binding sites. Therapeutic peptides from Faresyl Synthetase (Sequence ID Nos. 1 to 41) and therapeutic peptides from Hydroxy-Methyl-Glutaryl Coenzyme A Reductase (Sequence ID No.s 42-95). These peptides attenuate two key enzymes of cholesterol synthesis, and are therapeutically used in patients with high cholesterol levels.
S: Example No. 3 The renin angiotensin system and particularly the angiotensin-converting enzyme (ACE) are a continuous focus of antihypertensive drug development. Renin, angiotensin I and II as well as ACE are also promising targets for peptide therapy. Therapeutic use of synthetic analogs to the signal sequences of any of these proteins will lead to decreased 14b IVL96 ON XH/X1] 60:11 HMd TO, SO/TT blood pressure. Since in most cases hypertension is a chronic condition the therapeutic use of renin angiotensin or ACE signal peptide vaccines is a preferable method of treatmjent- I EFxamole No. 4 *5 S S
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For the acute treatment of myocadial inarction; thempeinc peptides from Plasmzinogen Activator Inhibitor (PAY-I1) (Sequence ID Nos. 173 to 194) hid Plasmiinogen Activator Inhibitor 2 (PAI-2) (Sequence ID Nos. 195-214) arm used to block the physiological effect of plasiinogen activator inhibitor, enhace plasminogen activation andtereby promote fibrinolysis. Thw preferred terapeutic application of the peprides in this case is the intravenOus injection of the peptides.
ExamDle No. s The following poteins' signal sequences ame derived from the method of this invention and are used for diagnostic as well as thmrpeutic purposes as described above.
Farnesyl Syntietase: HYdrOXY-MethYl-GlutarYl Coenzyme A Reductase: Gonadoliberin Precursor Plasmninogen Activator Inhibitor 1 Plasiigen Activator Inhibitor 2 Herpes Virus I (HSV 1) Glycoprotein B Herpes Virus 2 (HSV 23, 2H) Glycoprotein B Treponeuza Pallidum Membrane Protein (EMPA) Islet Arnyloid Polypeptide Collagenase (Fibroblast h80 1).
Schistosoma Elastase Precursor Schistosomin Apolipoprotein Human Apolipoprotein Rhesus Hepatitis Delta Antigen Rev Protein HMV, Sly, VILV, OMVVS Corticotropin Releasing Factor Binding Protein Sequence Id Nos. I 41 Sequence Id Nos- 42 -163 Sequence Id Nos. 164 172 Sequence Id Nos. 173 194 Sequence Id Nos. 195 23 8 Sequence Id Nos- 239 244 Sequence Id Nos- 245 251 Sequence Id Nos-. 252 262 Sequence Id Nos. 263 268 Sequence Id Nos. 269 280 Sequen~ce Id Nos- 281 214 Sequence Id Nos, 215 297 Sequence Id Nos. 2,8 289 Sequence Id Nos. 290 295 Sequence Id Nos. 296 298 Sequence Id Nos. 299 348 Sequence Id Nos. 349 360 EXaple No.. 6 Cholesterol Measurement in Hep G2 Cells Exposed to MHG CoA Reductase Peptides: A. Selection of therapeutic oligopeptides for thes experiments SThe peptides were selected according to the method described herein. In brief, 6 oligopeptides corresponding to the hydrophilic amino acid maxima of human hydroxy-methyl-glutayl-CoA-reductase were selected according to the maximum hydrophilicity determining algorithm described herein. The following sequences were selected: 1 4c LE /9Z LL9Z BV E Z 3 A 0 3 UOS I I I OD S @I APO NVO t L L 0-9 L [tL96 ON YH/XLI 60:11 Ik! TO, GO/IT L N-SQEDEVREN-C U. N-ELSRESREGR-C Ill. N-RVLEEEENK-C G IV. N-QKCDSVEE-C V. N-.EETGINR.ERKVE-C
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Vi. N-EPEIELPREPRPNEE-C B. Materials and methods i. Rep G2 cells were seeded into six-well dishes at 30,000 cells/well in NEMsupplemented media with 10% FBS. Cells were gown to near cofluency and exposed to 1. media alone 11. Mevastatin 5p.Mol (Cholestrol-lowering Statin drug) and, 11I. HMG CoA Reductase peptides at 1, 10 and 100 pMol.
*ii.1 All treatments were carried out in triplicate. After 24 his the media was removed and saved ii. The cells were washed with I ml of PBS and combined with the media. The cells were harvested with I mld of 0. 1N NaOH.
*iv. Samples, both media and cells, were saponified with 0.5 ml 50% KOH, 3 nil ethanol, separately at 80'C for 2 hrs.
V. After cooling, the samples were extracted twice with petroleum ether and II: 15washed with NaOil.
i. The samples were then dried under nitrogen and suspended in 200 1 ethanol.
vi. 50 gIl of this suspension was used for determination of cholesterol.
Cholesterol was determined in the samples and standards using calorimetric assay (Sigma Kit).
viii. Protein was determined by Lowry's method and the results were excpressed as jgm cholesterol/mg protein.
C. Results 1. T7he following results were obtained: Peptide Treatmftt Cholesterol Zeta[ Cholesterol- Conatent Cholesterol oeipn (~.igin/mg f Control Media protein) Control 152.1 39.0 66.5 6.5 218.6 35.0 Mevastatin pMol 124.4 4.4 57.5 5.2 192.0± 70 18.0 I 1 A 92.5 4.7 65.2 ±4.0 15937± 5.6 28-0 Mol 88.6 ±1.6 60-6 0.5 149.1 2.0 30.0 10 P. 94.0± 4.0 61.1 ±2.4 155-3 ±6A4 30.0 /YE 1 9z BVZG z 9 A 2Y tLY 0~ S e2 sI Io10 S 1A2 0:V4V L; LL VL U-9 -II [VL96 ON XH/XL] 60:IT IiIA TO, GO/TT P\WsDdCRhlmSII lla~~~Prr(~l~ad~s~r~WID I
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Cr C. CC.r 1 1 MCI 2 1 1 p 94.0 8.3 64.3±4.2 158.3±6-3 29.0 Mol 85.0f± 8.4 63.7±9.5 148.6±11.8 33.0 10 p 86-0 ±4.7 59.0±6.0 146.9±8.9 34.0 Mol 100 1i1 CI_ 3 1 1 p 137.3 4.5 64.0 ±27 201.3±3.3 10.0 Ml 135.0 4.5 65.5 L 4.7 200.7 9.0 10.0 10 p 135.0 7.0 65.0± 1.4 200.5±5.4 10.0
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100 i Mol PeDtide Treatment Cholestcrol Total Cholesterol- .Contenr Cholesterol LoweWJDn in Cell Media (Pg/gmg of Control 32rotei) Control 151.0± 7.8 50.8 ±2.5 202.0 53 Mevastatn gMol 125.0 ±4.6 37.S±3.0 162.6±7.6 19.0 4 1 1 p 134.7± 3.2 50.4 ±2.5 184.3±55 Mal 126.1 4.2 49.0 ±1.0 175.2 ±3.8 10.0 10 10 p 127.7±9.3 53.8±0.5 181.7±9.3 Mo 1 100 pL Mal 1 1 R 140.7 8.6 56.8±1.0 197.0±9.2 Mol 149.0 ±4.4 50.7 t1.0 200.015.0 0.0 10 p 161.7 23.5 48.0±1.6 210.0±25.0 0.0 Mo 100 p Mal 6 1 1 p 144.3 7.5 47.4±0.5 192.0±.8.0 Mel 136.0 12.2 48.0±3.4 184.0±8.4 10 p 132.0 4.4 50.4±1.0 182.4±4. W 1 100 v Mol D. Evaluation i. The following conclusions were drawn from this experiment: 14e 12 ILZ qVZ6 z 19+! 8 ALP3 U 0LY SB I I103 a IAAOS!IIO4sa! V 0JVOL: L[L 0 -LL [L96 ON XH/X1] 60:TT IHJ TO, 0O/TT I. Oligopeptides analogous to the hydrophilic maxima of a protein sequence can be used therapeutically.
II. The sequence of these therapeutic peptides can be determined for a protein with known amino acid sequence with the help of a computer algorithm for hydrophilicity.
III. This is the first time that a therapeutic peptide has been determined solely from applying the invention described herein.
IV. The HMG-CoA Reductase protein was chosen at random. It is conceivable that the method described herein is applicable to any other protein and, 10 therefore, has broad applications for medicine and for human health.
Throughout this specification and the claims which follow, unless the context requires S: otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers or steps but not the exclusion of any other integer or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge in Australia.
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S 0 S 5 00 S 6e 0 Figure 4: Direct Peptide Interception Therapy (Direct PIT) Methods For Identification, Design. Development and Therapeutic Use of Synthetic Analogs to Signal Ollgopeptldee In Peptide Interception Therapy ao Competitive Inhibitors Decreasing or Blocking Selected Protein Action 6eiectlon of Protein In Coinuter Databa94 Identification of Hydroplaylicity Maxima by Using *Hydrophylicity Algorithm *Surface Probability Algorithm *Any Algorithm In Which Values Are Assigned to Amino Acid Residues In the Following Way: Charged Amino Acids :1 Uncharged Polar Amino Acidc Nonpolar Amino Acids Any Combination of the Above Identify Signal Oligopeptides by Selecting Hydroph fI IftV Maxima of Protein Syntesie SnthticAnalogs to Signal Oligopeptides, (TheapeticPeptides) In Vitro and In Vivo Testing of TherapeuLic Peptidos Specific Competitive Inhibitors for Selected Protein Action (Test Positive [i~ialTestng of Therpec Peptides Clinical Use of Direct PIT Preferentially for, but Not Limited to *A'nute Therapy *High. Therapeutic Dosages *Intravenous Application Test Nepat-ve Optimization of Therapeutic Peptide Size or Sequence by Amino Acid Residue Substitution. Deletion.
Insertion etc.
Figure 5 :-Indirect Peptide Interception Therapy (Indirect PIT) Methods for Analogs to Identificstion. Design, Development and Therapeutic L199 of Synthetic Signal Ou1gopeptides, In Peptide Interception Therapy as Vaccines to Stimulate a Specific Immune Response Which Decreases or Blocks Selected Protein Action Selection of Protein In Computer Databae Identification of Hydrophyliefty Maxima by Using Hydrophylclt Algorithm -Surface Probability Algorithm Any Algorithm In Which Values Are Assigned to Amino Acid Residues In the Following Way: Charged Amino Acids Uncharged Polar Amino Acids Nonpolar Amino Acids I Any Combination of the Above Identify Signal Oligopeptides by Selecting Hydrophyictty Maxima of Proti
Q
Synthesize Synthetic Analogs' to Signal Oigopeptides (Therapeutic Peptides) Render Therapeutic Peptides Immunogenic by Means of Haptens o r Other Conventional Methods 2 Design Immunogenicity by Selecting Corresponding Xenoiogous Signal Oligopeptides from Different Species (Immunogenicity is Based on Variation of Amino Acid Residues Within Xenoiogous I ~Signs.' Oligopeptidle) J Sthiz Synthetic Analogs to Xe.,oiogous Signal Cligopeptidles (herapeutic 'Peptides)% In Vitro And In Vivo Testing of Therapeutic Peptides Vaccines Stimulating Specific Immune Response -Interceptinq Selected Protein Action- :Test Positive Clinical Testing of Therapeutic Peptides Te s Ne a te Spt imization of Therapeutic Peptide -Ize or Sequence by Amino Acid Residue Substitution. Deletion.
nsertion etc. Teoting of Analogs to Corresponding Signal Sequences from Additional Species. If Necessary.
Sequence Analysis of Selected Protein from Additional Species.
Clinical Use of Indirect PIT Preferentially for. but Not Limited to *Chronic Therapy *Preventive Therapy *Subcutaneous Application *Intracutaneus Application Figure 6. Peptide Regulation Therapy (PRT) Methods For Identification. Design, Development and Therapeutic use of Synthetic Analogs to Signal Oligopeptldes In Peptide Regulation Therapy as Negative Feed- Back Regulators for the Synthesis Rate of Selected Proteins bseiection of Profsi In Computer Datbs Identification of Hydrophylicity Maxima by Using Hydrophylichty Algorithm Surface Probability Algorithm Any Algorithm In Which Values Are Assigned to Amino Acid Residues In the Following Way: Charged Amino Acids :o Uncharged Polar Amino Acids zo Nonpolar Amino Acids Any Combination of the Above ieSyntesienthetic Analogs to Signal Oligopeptides (Therapeutic Peptides) InVtoan nVvoTsig f'hraetcPetdsasNgtv FodBc Reuatr fo h ythssRt of th Seetdrti Tes Poiie.*iNeit Clnia Tetn.fOt.z lnofTeaetcPpieSz T Peenstivehrp etrlAplcto Figure 7 ;1 Signal Oligopeptides as Antigens for the Development of Highily Specific and Precisely Characterized In Vitro Diagnostic Assays Methods For identiflcation. Design. Development and Use. of Synthetic Analogs to Signal Oflgopeptide so Antigoe for the Production of Specific Antibodies with Precise Predefined Binding Characteristics selection of Protein In Cornuter Databas~e 4* .1 9 9* Identification of ilydrophylicity Maxima by Using *Hydrophylicity Algorithm *Surface Probability Algorithm *Any Algorithm In Which Values Are Assigned to Amino Acid Residues In the Following Way: Charged Amino Acids Wicharged Polar Amino Acids >Nonpolar Amino Acids *Any Combination of the Above Synthesize Synthetic Analogs to Signal Oligopeptides (Anti ens) Immunization of Animals with Antigens and Production of Polyclonal and Monoclonal Antibodieo According to Stand~ard Procedures Testing of Antibodies AantSynthetic Oligopeptide Used as Antigen and Against Entire Protein Use of These Antibodies for the Development of Diagnostic Assays with Precise and Predefined Specificity and Epito p. Characterization- Figure 8: Amino Acid Sequence Selection and Therapeutic Design' of Peptide Vaccines For Indirect Peptide Interception Therapy Exemplified for the the Development of Giucagon Vaccines for Indirect Peptide Interception Therapy of Diabetes Mellitus Identify Signal Oligopeptidee From Hydrophyllcity Maxima From Human Glucagon Precursor Sequence Identify Corresponding Signal Oligopeptide from Glucagon Precursor Sequences In Different Species Use Evolutionary Tree to Determine Relative Distance at Available Glucagon Sequences to Human Sequence. The Evolutionary Distance Is Positively Correlated with Degree of Amino Acid Variation and, thus. with the Antigenicity of the Selected Protein WIT .OIAC Caeg of av~slm Cuq .1 *~.ImEf Cop or Gm.JOM to 1 fr m.QALX co" 0 awme De 4 0 a.
a a a a. a.
a a a.
a a a a a a a.
a a. a.
a a a *9 Select Therapeutic Peptide Sequence AmonSO The Corresponding Signal Oligopeptide Sequences According to the Following Criteria I.Moderate Therapeutic Immune Response Desired: Design of Therapeutic Peptides Analogous to Signal Sequences From Species Genetically Close to Humans Mammals) *>Amino Acid Residue Variation Within Therapeutic Peptide (Vaccine) Must Be Sufficient to Cause immune Response *Therapeutic Use of Immune Response 2. Strong Therapeutic Immune Response Desired: Design of Therapeutic Peptides Analogous to Signal Sequences From Species Genetically More Distant to Humans Fish. Yeast) More Amino Acid Residue Variation Within Signal Sequence *>Greater Antigenicity of Therap.Poptide ->Higher Therapeutic Efficiency 23 The following specific sequences are claimed In this patent: FARNESYL
SYNTHLTASE
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Claims (7)
1. A method for producing therapeutic peptides as vaccines in the prevention of human disease caused by protein, the method comprising: a) identifying a protein responsible for causing human disease; b) identifying one or more signal oligopeptide sequences within the structure of the disease causing protein, the one or more signal oligopeptides representing the amino acid sequences of maximum hydrophilicity and/or maximum surface probability, and/or maximum electrical charge of the 10 protein; and c) synthesizing one or more vaccine oligopeptides, the vaccine oligopeptides having the amino acid sequences corresponding to the amino acid sequences of the signal oligopeptides identified in b). 15 2. The method of claim 1 further comprising an evolutionary comparison step, wherein one or more species of animals in an evolutionary chain are selected to produce different vaccine oligopeptides to the same disease causing protein.
3. The method of claim 1 or 2 further comprising an optimization step, wherein the 20 one or more vaccine oligopeptides are manipulated through one or more amino acid oi: residue substitutions, amino acid deletions, or amino acid insertions, or any combination thereof, to produce an optimized immunogenic response in vaccinated humans. 25 4. The method of claim 3 wherein the immunogenic response of the vaccine 0 •oligopeptides in humans is enhanced by repetition of the vaccine oligopeptides to 1. form a linear polypeptide. The method of claim 3 wherein the immunogenic response of the vaccine oligopeptides in humans is enhanced by repetition of the vaccine oligopeptides to form a cyclic polypeptide.
6. The method of claim 3 wherein the immunogenic response of the vaccine oligopeptides in humans is enhanced by coupling one or more of the vaccine oligopeptides to an immunogenic protein or non-protein haptens.
7. The method of any one of claims 1 to 6 wherein the amino acid sequence of maximum hydrophilicity are identified by a hydrophilicity determining algorithm.
8. The method of any one of claims 1 to 7 wherein amino acid sequences of maximum surface probability is identified by a surface probability determining algorithm.
9. The method of any one of claims 1 to 8 wherein amino acid sequences of maximum electrical charge is identified by an electrical charge determining algorithm. 3 83 uJ 83 1E /EI 19 Z at Z6 Z 9 a AU23 LL9 S 1103 S aOS Ii A S a VO L L 0- -LL [j'L96 ON XH/XI] 60:11 IUA TO, SO/TT A therapeutic peptide produced according to the method of any one of claims 1 to 9.
11. Methods, therapeutic peptides produced thereby, or signal oligopeptides substantially as herein described with reference to the examples and figures. 0 00 *0 W699 S 00#*0 0 4, 5~ 00*9 0 00*04S *0*0 6 DATED this 11Ith day of May, 2001 MATTHIAS RATH By his Patent Attorneys DAVIES COLLISON CAVE E E [L9z 8vzs z L 9 IC /E LY~ V~6 B~2 UOS I 1 10 so I Aao:!ja I L 1-9 -LIt
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU81834/98A AU735298B2 (en) | 1994-01-14 | 1998-08-24 | Hydrophilic signal oligopeptides and methods of therapeutic use |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US182248 | 1994-01-14 | ||
| AU16810/95A AU1681095A (en) | 1994-01-14 | 1995-01-12 | Hydrophilic signal oligopeptides and methods of therapeutic use |
| AU81834/98A AU735298B2 (en) | 1994-01-14 | 1998-08-24 | Hydrophilic signal oligopeptides and methods of therapeutic use |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU16810/95A Division AU1681095A (en) | 1994-01-14 | 1995-01-12 | Hydrophilic signal oligopeptides and methods of therapeutic use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8183498A AU8183498A (en) | 1998-10-08 |
| AU735298B2 true AU735298B2 (en) | 2001-07-05 |
Family
ID=3706710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU81834/98A Ceased AU735298B2 (en) | 1994-01-14 | 1998-08-24 | Hydrophilic signal oligopeptides and methods of therapeutic use |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU735298B2 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4554101A (en) * | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
-
1998
- 1998-08-24 AU AU81834/98A patent/AU735298B2/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4554101A (en) * | 1981-01-09 | 1985-11-19 | New York Blood Center, Inc. | Identification and preparation of epitopes on antigens and allergens on the basis of hydrophilicity |
Also Published As
| Publication number | Publication date |
|---|---|
| AU8183498A (en) | 1998-10-08 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FGA | Letters patent sealed or granted (standard patent) |