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GB2157698A - Enzyme inhibitor - Google Patents
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GB2157698A - Enzyme inhibitor - Google Patents

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GB2157698A
GB2157698A GB08511138A GB8511138A GB2157698A GB 2157698 A GB2157698 A GB 2157698A GB 08511138 A GB08511138 A GB 08511138A GB 8511138 A GB8511138 A GB 8511138A GB 2157698 A GB2157698 A GB 2157698A
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Prior art keywords
pro
lys
ala
inhibitor
ile
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GB8511138D0 (en
GB2157698B (en
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Terence Seward Baker
Michael Joseph Powell
Richard Charles Titmas
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Boots Celltech Diagnostics Ltd
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Boots Celltech Diagnostics Ltd
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Priority to GB08511138A priority Critical patent/GB2157698B/en
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C12Q1/37—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase involving peptidase or proteinase
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/581—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with enzyme label (including co-enzymes, co-factors, enzyme inhibitors or substrates)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G01N33/743—Steroid hormones

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Food Science & Technology (AREA)
  • Cell Biology (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

An inhibitor for an enzyme capable of clotting milk wherein the inhibitor is selected from the following group of compounds P-ser-Z-ala-Q, P-val-Z-val-Q or P-asp-Z-ala-Q wherein Z is statine or Z is a diradical of the general formula <IMAGE> wherein <IMAGE> (a retroinverso peptide analogue) and R2 is -CH2CH2CH2CH3, -CH2CH2S CH3 or -H, and wherein P is selected from A-, his-A-, pro-his-A-, his-pro-his-A-, pro-his-pro-his-A-, his-pro-his-pro-his-A-, and arg-his-pro-his-pro-his-A-, wherein A is a leucine or valine radical, and wherein Q is selected from -B, -B-pro, -B-pro-pro, -B-pro-pro-lys, -B-pro-pro-lys-lys, and -B-pro-pro-lys-lys-asn, wherein B is an isoleucine or leucine radical.

Description

SPECIFICATION Enzyme inhibitor This invention relates to an enzyme inhibitor, and in particular to an inhibitor for an enzyme capable of clotting milk.
The enzyme inhibitor described and claimed herein is useful, for example, in the preparation of a conjugate molecule for use in an enzyme inhibitor labelled immunoassay, such as is described in British patent application 8400921 (GB2135773A) of which this is a division.
According to the present invention we provide an inhibitor for an enzyme capable of clotting milk wherein the inhibitor is selected from the following group of compounds; P-ser-Z-ala-Q, P-val-Z-val-Q or P-asp-Z-ala-Q wherein Z is statine or Z is a diradicai of the
wherein, R1 is -CH2-NH,
(a retroinverso peptide analogue) and R2 is -CH2CH2CH2CH3, -CH2CH2SCH3 or -H, and wherein P is selected from A-, his-A-, pro-his-A;; his-pro-his-A-, pro-his-pro-his-A;; his-pro-his-pro-his-A;; and arg-his-pro- his-pro-his-A-, wherein A is a leucine or valine radical, and wherein Q is selected from -B, -Bpro, -B-pro-pro, -B-pro-pro-lys, -B-pro-pro-lys-lys, and -B-pro-pro-lys-lys- asn, wherein B is an isoleucine or leucine radical.
The inhibitor may be a synthetic polypeptide.
Preferably Rl is
Preferably the inhibitors of the invention are synthetic polypeptides of the general formulae; leu-asp-Z-ala-ile-pro-pro-lys-lys, his-leu-asp-Z-ala-ile-pro-pro-lys-lys, leu-ser-Z-ala-ile-pro-pro-lys-lys or his-leu-ser-Z-ala-ile-pro-pro-lys-lys, wherein Z is as previously defined. Preferably Z is statine.
The following inhibitors of the invention are thus especially preferred his-leu-ser-sta-ala-ile-pro-pro-lys-lys leu-ser-sta-ala-ile-pro-pro-lys-lys The C-terminal and/or the N-terminal amino acid of any of the inhibitors may be substituted. For example the C-terminal amino acid may be esterified and/or the N-terminal amino acid may be acylated.
Some embodiments of the invention are now described by way of Examples.
Two synthetic inhibitors were prepared.
(Unless otherwise stated reagents were obtained from Sigma Chemical Co. Ltd.).
The inhibitors include the amino acid statine (4(S)-amino, 3(S)-hydroxy, 6 methylhaptanoic acid) which was prepared in a protected form by the synthesis described in the scheme given below, in the scheme, Z is a benzyloxycarbonyl protecting roup, DIBAL represents diisobutylaluminium hydride, THF represents tetrahydrofuran THP represents tetrahydropyranyl and FMOC represents 9-fluorenylmethoxy- carbonyl.
The reactions described in above scheme were carried out as follows: (a) To an ice-cooled solution of Z-S-leucine I (299, 0.11 mop) in ether (200ml) was added a solution of diazomethane in ether ( 6g, 0.limol). After the evolution of nitrogen had ceased, the mixture was concentrated in vacuo to an oil (compound II). Compound II was used in the next reaction without purfication.
(b) To a vigorously stirred solution of compound 11 (14.49g, 48.9mmol) in dry toluene (210ml), was added a 1M solution of diisobutylaluminium hydride (DIBAL) (124ml, 124mmol) in hexane at -70 C under nitrogen. After 6 mins, methanol (12ml) was added followed immediately by saturated Rochelle salt solution (500ml). The reaction mixture was allowed to warm up to room temperature and was then extracted with ether (3x300ml). The organic layers were sequentially washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to an oil. The yield of compound Ill was 7.99. The compound was stored at -200C and used as soon as possible without further purification.
(c) To diisopropylamine (19.2ml, 137mmol) in drytetrahydrofuran (THF) (45ml) in a dry ice/chloroform bath under nitrogen was added 1.6M n-butyllithium in hexane (85.62ml, 137mmol) by syringe. After one hour, the bath was replaced with a dry ice/ethanol bath and dry ethyl acetate (13.4ml, 13.7mmol) was added slowly whilst keeping the temperature at about -70 C. After the addition, the reaction mixture was left to stir for 15 minutes at which time compound Ill (22.89, 92mmol) in dry THF (90ml) was added whilst keeping the temperature below -65 C. The reaction mixture was stirred for 5 minutes at which time 1M hydrochloric acid (300ml) was added and the reaction mixture was allowed to warm up to room temperature and was extracted with ethyl acetate (3x200ml). The organic layers were sequentially washed with saturated sodium chloride solution (1 litre), dried over sodium sulphate and concentrated to an oil of crude material. The yield containing compound IV was 31g. The material was purified twice by silica gel chromatography.
First chromotraphy conditions 31g of the crude material was applied onto 5009 of Merck 9385 silica gel (RTM). (2 litres chloroform, followed by 2 litres chloroform/ethyl acetate (95.5)). This yielded 269 of the unseparated two isomers of compound (IV) (3R, 4S and 3S, 4S) having an Rf of 2.0 (20% ethyl acetate in toluene).
Second Chromatography Conditions 129 of partially purified compound IV was applied onto 200g of Merck 9385 silica gel. (1 litre toluene/ ethyl acetate (95:5) followed by 1 litre toluene/ethyl acetate (9:1) followed by 1 litre ethyl acetate (85:15) followed by 2 litres toluene/ethyl acetate (4:1)). Sixty 50ml fractions were collected.
2.49 of the required isomer of compound IV (3R,4S) with an Rf of 0.23 was separated from 1.1g of the unrequired isomer (3R, 4S) having an Rf of 0.17 (Elution with 20% ethyl acetate in toluene).
(d) To compound IV (2.9g, 8.6 mmoles) in dry dioxan (30ml) was added, with stirring, dihydropyran (4ml, 51.6 mmoles) followed by about 2mg of p-toluenesulphonic acid monohydrate. After two hours stirring in the dark H.P.L.C. showed that the reaction was complete. The HPLC was conducted using an ultrasphere reverse phase HPLC column (30cm x 4mm). Flow 1ml amino'; Solvent A: water; Solvent B: methyl cyanide; X:260nm. (Omin-60% A, 40% b; 15 min 20% A, 80% B, 20 min-20% A; 80% B). The reaction was complete when the peak due to compound IV, with a retention time of 11 minutes, disappeared.
The reaction mixture was well shaken with saturated aqueous sodium hydrogencarbonate (300ml) and extracted with dichloromethane (3 x 200 ml). The organic layer was washed with saturated aqueous sodium hydrogencarbonate (1 x 300ml), and water (1 x 200ml) and was concentrated to an oil. The oil was placed in a high vacuum (about 10-- Torr) overnight to remove excess dihydropyran. The yield of compound V (with dioxan still present) was 3.89. The compound was used without further purification.
(e) To compound (V) (about 2.79, about 6 mmoles) in dioxan (35ml) was added with stirring 1M aq.
sodium hydroxide (35ml). A clear solution formed after 30 minutes and HPLC showed reaction to be complete after 2 hours. The conditions and protocol of HPLC were as in (d) above 20 ul of the reaction mixture was mixed with 2 ul of Aristar glacial acetic acid and 10 ul of the mixture thus formed was injected onto the column. The reaction was complete when the peak due to compound V, with a retention time of 17 minutes, disappeared. Water (50ml) was added and the aqueous solution was washed with ether (3 x 50ml), ethyl acetate (2 x 50ml) and its pH was adjusted with concentrated hydrochloric acid to pH 6.00. The resultant oily solution was immediately extracted with ethyl acetate (4 x 75ml). Immediate extraction is necessary because of the lability of the tetrahydropyran (THP) group.The organic layer was washed with water (1 x 50ml), dried over sodium sulphate and evaporated to an oil.
The yield of compound VI was 1.929. The compound was used without further purification.
(f) To compound (VI) (1.920g, 4.7 mmoles) in methanol (25ml) was added 5%Pd/C catalyst (0.50g). Hydrogen was passed through the mixture, with stirring for one hour. The reaction mixture was filtered through celite and washed with 10% water in methanol (50ml). The collected filtrate was concentrated to a solid. TLC ethanol/hexane, 2:1 v/v) developed with a ninhydrin spray gave a product spot at Rf 0.13.
The yield of compound VII was 1.1 1g. The compound was used without further purification.
(g)To a stirred solution of compound VII (0.5269, 2mmol) in 10% (w/v) aq. sodium carbonate (5.4ml) and dioxan (2ml), was added 9-f!uorenylmethoxycarbonyl chloride FMOC-C1 (0.544g, 2.lmmol) in dioxan (5ml) over a period of 20 minutes. During this addition more 10% (w/v) aq. sodium carbonate (13ml) was added over the same period in order to maintain a clear solution. After 60 minutes stirring, water (20ml) was added and the mixture was concentrated to about half its original volume. More water (200ml) was added before the mixture was washed with ether (4 x 200ml). The aqueous layer was adjusted carefully with hydrochloric acid to pH6.5 and then immediately extracted with ethyl acetate (4 x 150ml). The organic layer was washed with water (100ml), dried over sodium sulphate and concentrated to a solid (0.740g).
The product compound Vlil was purified by reverse phase chromatography, under the following conditions: 2.5cm x 50cm column packed with Lichroprep RP18 30% methanol/water - 100% methanol over 2 litres.
100% methanol 1 litre 20ml fractions were collected.
Fractions 101-118, which contained product, were pooled, concentrated to half its original volume, added to water (500ml) and extracted with dichloromethane (3 x 500ml). The organic layer was washed with water (100ml), dried over sodium sulphate and concentrated to a solid (0.4509).
Nmr (CDCl3): T 9.0 (6H,d, (CH3)2CH2); 8.6 - 8.0 (9H,M,THP); 7.4 (2H,d, CH2 - CO2H); 6.5 (2H, d, CH2OC(O)); 2.7 - 2.0 (8H,M (c6H4)2CH2; 1.1 (1H, 6brs, CO2H).
The protected statine produced by the above steps (a)-(g) was used in the preparation of a polyamide supported, partially protected decapeptide IX essentially by the method described by Atherton et at (Proc.
17th European Peptide symp., eds. Blaha, K. and Malon, P. pp 241-246 (1982)).
(OtBu = tertiary butoxy, TFA = trifluoroacetic acid (P) = polamide support.
A polyamide supported, partially protected nonapeptide X was also prepared, using the same method.
(Z = benzyloxycarbonyl).
Compounds X and IX are inhibitors of the activity of chymosin.
Enzyme inhibition data was obtained using synthetic peptide substrates containing a chromophoric nitrophenyla- lanine residue in the position of the scissile bond so that hydroysis can be followed spectrophotometrically. (The chromogenic peptide substrates were supplied by Dr.B.M.Dunn, Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, U.S.A.). Hydrolysis was followed by 300 nm and the substrate can be used at any pH value (usually between 2-6) at which the enzyme is active. Kinetic parameters for the hydrolysis of a chromogenic peptide substrate by different types of mammalian aspartic proteinases have been reported J. Kay, M. J. Valler and B.M.Dunn, Naturally-occurring inhibitors of Aspartic Proteinases in Proteinase Inhibitors; N.Katunuma, H. Umezawa and H. Holzer Eds., 1983 Springer-Verlag, Berlin (in press).The compound Ac-his-leu-ser-stat-ala-ile-pro-pro-lys-lys was shown to exhibit a K of 0.006 (,uwM) at pH 3.1 with Endothia parasiticaprotease.
Bibliography 1. Evolution in the Structure and Function of Carboxyl Proteases. Jordan Tang Mol. Cell. Biochem., 1979, 26(2) 93-109.
2. The inactivation of Pepsin by Diazoacetyl-norleucine Methyl Ester, T.G. Rajagopalan, W.H.Stein and S.
Moore J. Biol. Chem 1966, 241, 4295-4297.
3. Acid Proteases, Structure, Function and Biology, Edited by Jordan Tang, Plenum Press, New York and London, 1977.
4. Proteinases and their inhibitors, Structure, Function and Applied Aspects. Proc. Intern. Symp. Portoroz, Yugoslavia, 1980. Published 1981, Perganon Press.
5. Effect of Pepstatin on Acid Proteases T. Aoyagi, S. Kunimoto, H. Morishina, T. Takeuchi and H. Urnezawa, J. Antibiot., 1971 24(10), 687-694. 6. Synthesis of Analogues of the Carboxyl Protease inhibitor Pepstatin. Effect of Structure on Inhibition of Pepsin and Renin. D.H.Rich, E.T.0. Sun and E. Uln. J. Med.
Chem. 1908, 23 27-33.
7. Mechanism of Inhibition of Pepsin by Pepstatin. Effect of Inhibitor structure on dissocition constant and Time-Depedent Inhibition. D.H.Rich and E.T.O. Sun, Biochm. Pharmacol., 1980, 29 2205-2212, 8. New Renin Inhibitors homolgous with pepstatim M. Eid., G. Evin, B. Castro, J. Menard and P. Corvol., Biochem J 1981, 197 465-471. 9. The active Site of Acid Proteinases. T.L.Blundell, H.B.Jones, C. Khan, G.
Taylor, B.T. Sewell, L.H.Pearl and S.P. Wood. FEBS Proc, 1980, 60, 281-288.
10. Synthesis of a 3-oxo-4(s)-amino acid analog of pepstatin. A New Inhibitor of Carboxyl (acid) protreases. D.H.Rich, A.S.Boparai and M.S.Bernatowicz, Biochem. Biophys, Res. Commun. 1982, 104(3), 1127-1133.
11. Spin-labelled Pepstatin Binding to Pepsin. A study by Eiectron spin Resonance and Nuclear Magnetic Resonance. P.G.Schmidt, M.S.Bernatowicz and D.H. Rich Biochemistry, 1982, 21, 1830-1835.
12. Solid-phase synthesis of a soluble pepstatin derivative suitable for the rapeutic use. B.M.Austen, T.F.
Ford, D.A.W. Grant and J. Hermon-Taylor. Bioscience Reports, 1982, 2, 427-432.
13. Inhibition of Cathepsin D by synthetic Oligopeptides. T-Y. Lin and H.R.Williams, J.Biol. Chem., 1979, 11875-11883.

Claims (8)

1. An inhibitor for an enzyem capable of clotting milk wherein the inhibitor is selected from the following group of compounds P-ser-Z-ala-Q, P-val-Z-val-Q or P-asp-Z-ala-Q wherein Z is statine or Z is a diradical of the general formula
wherein R1 is -CH2-NH-,
-S-CH2,
(a retroinverso peptide analogue) and R2 is -CH2CH2CH2CH3, -CH2CH2S CH3 or -H, and wherein P is selected from A-, his-A-, pro-his-A;; his-pro-his-A-, pro-his-pro-his-A,; his-pro-his-pro-his-A-, and arg-his-pro- his-pro-his-A-, wherein A is a leucine or valine radical, and wherein Q is selected from -B, -Bpro, -B-pro-pro, -B-pro-pro-lys, -B-pro-pro-lys-lys, and -B-pro-pro-lys- lys-asn, wherein B is an isoleucine or leucine radical.
2. An inhibitor according to claim 1 wherein R1 is
3. An inhibitor according to claim 1 or 2 selected from one of the following group of compounds leu-asp-Z-ala-ile-pro-pro-lys-lys, his-leu-asp-Z-ala-ile-pro-pro-lys-lys, leu-ser-Z-ala-ile-pro-pro-lys-lys and his-leu-ser-Z-ala-ile-pro-pro-lys-lys, wherein Z is as defined in claim 1.
4. An inhibitor according to claim 3 wherein Z is statine.
5. A compound having the amino acid sequence his-leu-ser-sta-ala-ile-pro-pro-lys-lys.
6. A compound having the amino acid sequence leu-ser-sta-ala-ile-pro-pro-lys-lys.
7. An inhibitor according to any one of the preceding claims wherein the C-terminal amino acid is esterified and/or the N-terminal amino acid is acylated.
8. An inhibitor substantially as hereinbefore described.
GB08511138A 1983-01-31 1985-05-02 Enzyme inhibitor Expired GB2157698B (en)

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Application Number Priority Date Filing Date Title
GB08511138A GB2157698B (en) 1983-01-31 1985-05-02 Enzyme inhibitor

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GB838302622A GB8302622D0 (en) 1983-01-31 1983-01-31 Immunoassay
GB838320164A GB8320164D0 (en) 1983-01-31 1983-07-26 Immunoassay
GB08511138A GB2157698B (en) 1983-01-31 1985-05-02 Enzyme inhibitor

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GB2157698A true GB2157698A (en) 1985-10-30
GB2157698B GB2157698B (en) 1986-07-16

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GB2157698B (en) 1986-07-16

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