US2002147301A1PendingUtilityA1
Parevins and tachytegrins
Assignee: INTRABIOTICS PHARMACEUTICALSPriority: Jul 6, 1995Filed: May 24, 2001Published: Oct 10, 2002
Est. expiryJul 6, 2015(expired)· nominal 20-yr term from priority
Y02A50/30A61L 12/14C07K 7/08A61K 38/00A01N 37/46
44
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Claims
Abstract
The present invention provides a new class of broad-spectrum antimicrobial peptides effective against a wide variety of microbes, including bacteria, viruses, retroviruses, fungi, yeast and protozoa.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound composed of 11-24 amino acid residues comprising the amino acid sequence:
A 1 -A 2 -A 3 -C 4 -C 5 -C 6 -A 7 -C 8 -A 9 -A 10 -A 11 -A 12 -C 13 -A 14 -C 15 -C 16 -C 17 -A 18
or a pharmaceutically acceptable salt or an N-terminal acylated or C-terminal amidated or esterified form thereof, said compound being either in a linear or in a disulfide-bridged form, wherein:
each of A 1 -A 3 is independently present or not present, and if present each is independently a basic, hydrophobic, polar/large, or small amino acid;
each of C 4 and C 17 is independently present or not present, and if present each is independently selected from the group consisting of cysteine, homocysteine, penicillamine, a basic amino acid, a hydrophobic amino acid, a polar/large amino acid and a small amino acid;
C 5 is selected from the group consisting of cysteine, homocysteine, penicillamine, a basic amino acid, a hydrophobic amino acid, a polar/large amino acid and a small amino acid;
each of C 6 , C 8 , C 13 and C 15 is independently selected from the group consisting of cysteine, homocysteine, penicillamine, a basic amino acid, a hydrophobic amino acid, a polar/large amino acid, a small amino acid and an acidic amino acid;
C 16 is selected from the group consisting of cysteine, homocysteine, penicillamine, a hydrophobic amino acid or a small amino acid;
each of A 7 and A 14 is independently a hydrophobic or a small amino acid;
A 9 -A 12 taken together are capable of effecting a β-turn when contained in the compound and at least one of A 9 -A 12 is a basic amino acid;
A 18 is present or not present, and if present, is a basic, hydrophobic, polar/large, or small amino acid;
at least about 15% to about 50% of the amino acid residues composing said compound are basic amino acids; and
said compound has a net positive charge of at least +1 at physiological pH;
with the provisos that: (i) when one of C 4 , C 5 or C 6 is cysteine, homocysteine or penicillamine, the other two are other than cysteine, homocysteine and penicillamine;
(ii) when one of C 15 , C 16 or C 17 is cysteine, homocysteine or penicillamine, the other two are other than cysteine, homocysteine and penicillamine;
and (iii) at least one of C 4 , C 5 , C 16 or C 17 is cysteine, homocysteine or penicillamine.
2 . The compound of claim 1 which comprises two disulfide bridges.
3 . The compound of claim 2 , wherein one of said disulfide bridges links C 5 -C 16 and the other links C 8 -C 13 .
4 . The compound of claim 3 which is selected from the group consisting of:
and the C-terminal amidated forms thereof, wherein X is Har, x is D-Har, lower case letters represent D-amino acids and lines between C or c residues represent disulfide linkages.
5 . The compound of claim 2 , wherein one of said disulfide bridges links C 5 -C 8 and the other links C 13 -C 16 .
6 . The compound of claim 5 which is selected from the group consisting of:
and the C-terminal amidated forms thereof, wherein X is Har, x is D-Har, lower case letters represent D-amino acids and lines between C and c residues represent disulfide linkages.
7 . The compound of claim 2 , wherein one of said disulfide bridges links C 4 -C 17 and the other links C 8 -C 13 .
8 . The compound of claim 7 which is selected from the group consisting of:
and the C-terminal amidated forms thereof, wherein X is Har, x is D-Har, lower case letters represent D-amino acids and lines between C or c residues represent disulfide linkages.
9 . The compound of claim 1 which comprises one disulfide bridge.
10 . The compound of claim 9 in which said disulfide bridge links C 4 -C 17 .
11 . The compound of claim 10 which is selected from the group consisting of:
and the C-terminal amidated forms thereof, wherein X is Har, Z is MeGly and lines between C residues represent disulfide linkages.
12 . The compound of claim 9 in which said disulfide bridge links C 5 -C 16 .
13 . The compound of claim 12 which is selected from the group consisting of:
and the C-terminal amidated forms thereof, wherein X is Har, x is D-Har, lower case letters represent D-amino acids and lines between C residues represent disulfide linkages.
14 . The compound of claim 9 in which the disulfide bridge links C 8 and C 13 .
15 . The compound of claim 1 which is in the linear form.
16 . The compound of claim 1 in which at least one of A 1 , A 2 or A 3 is not present.
17 . The compound claim 1 in which A 1 , A 2 and A 3 are not present.
18 . The compound of claim 1 in which at least one of A 1 , A 2 or A 3 is a hydrophobic amino acid.
19 . The compound of claim 1 in which each of C 5 and C 16 is independently selected from the group consisting of cysteine, homocysteine, penicillamine, I, V, L, NLe, W, Y, F, A, S, G and T.
20 . The compound of claim 1 in which each of C 4 and C 17 is independently selected from the group consisting of cysteine, homocysteine, penicillamine, I, V, L, NLe, W, Y, F, A, S, G and T.
21 . The compound of claim 1 in which each of A 7 and A 14 is independently selected from the group consisting of I, V, L, NLe, W, Y, F, A, S, G and T.
22 . The compound of claim 1 in which one of A 9 or A 12 is R, K, Har, Orn or H and the other is I, V, L, NLe, W, Y, F, A, S, G or T.
23 . The compound of claim 1 in which all amino acids are in the D-configuration.
24 . The compound of claim 1 in which A 7 and A 14 are each independently a hydrophobic amino acid.
25 . The compound of claim 1 in which A 9 or A 12 is a hydrophobic amino acid or a small amino acid.
26 . The compound of claim 1 in which A 10 and A 11 are each independently selected from the group consisting of proline, a basic amino acid, a hydrophobic amino acid and a small amino acid.
27 . The compound of claim 1 in which each of C 8 and C 13 is independently cysteine, homocysteine or penicillamine.
28 . The compound of claim 1 in which A 9 -A 10 -A 12 is selected from the group consisting of: R-R-R-F, R-G-W-I, R-P-R-F, X-R-R-F, R-X-RF, R-K-K-W, R-X-R-Y, R-R-K-W, r-R-R-F, R-x-R-F, R-G-R-F, C-R-G-R, Y-C-G-R, V-P-R-R-F, K-P-K-F, V-G-R-F, R-P-R-I and R-Z-R-F, where X is Har, x is D-Har, Z is MeGly and r is D-Arg.
29 . The compound of claim 1 which is in the linear or disulfide-bridged form and which is selected from the group consisting of:
+M 1 !, 4 RGGRCLYCRRRFCVVCGR? , 19 (SEQ ID NO: 11 );? ! !RGGCRLYCRRRFCVVGCR? (SEQ ID NO: 12 );? ! !RGGRCLYCRRRFCIVCG? (SEQ ID NO: 13 );? ! !RGGCRLYCRRRFCIVGC? (SEQ ID NO: 14 );? ! !RGGGCLYCRRRFCVVCGR? (SEQ ID NO: 15 );? ! !RGGCGLYCRRRFCVVGCR? (SEQ ID NO: 16 );? ! !RGGRCLYCRGWICFVCGR? (SEQ ID NO: 17 );? ! !RGGCRLYCRGWICFVGCR? (SEQ ID NO: 18 );? ! !RGGRCLYCRPRFCVVCGR? (SEQ ID NO: 19 );? ! !RGGCRLYCRPRFCVVGCR? (SEQ ID NO: 20 );? ! !RGGRCVYCRRRFCVVCG? (SEQ ID NO: 21 );? ! !RGGCRVYCRRRFCVIGC? (SEQ ID NO: 22 );? ! !KGGRCLYCRRRFCVVCG? (SEQ ID NO: 23 );? ! !KGGCRIYCRRRFCVIGC? (SEQ ID NO: 24 );? ! !RGGXCLYCRRRFCVVC? (SEQ ID NO: 25 );? ! !RGGCXLYCRRRFCVIC? (SEQ ID NO: 26 );? ! !RGGXCLYCXRRFCVVCGR? (SEQ ID NO: 27 );? ! !RGGCXLYCXRRFCVIGCR? (SEQ ID NO: 28 );? ! !RGGRCVYCRXRFCVVCGR? (SEQ ID NO: 29 );? ! !RGGCRVYCRXRFCVVGCR? (SEQ ID NO: 30 );? ! !RGGRCLYCRKKWCVVCGR? (SEQ ID NO: 31 );? ! !RGGCRLYCRKKWCVVGCR? (SEQ ID NO: 32 );? ! !RGGRCLYCRXRYCVVCGR? (SEQ ID NO: 33 );? ! !RGGCRLYCRXRYCVVACR? (SEQ ID NO: 34 );? ! !RGSGCLYCRRKWCVVCGR? (SEQ ID NO: 35 );? ! !RGSCGLYCRRKWCVVGCR? (SEQ ID NO: 36 );? ! !RATRCIFCRRRFCVVCGR? (SEQ ID NO: 37 );? ! !RATCRIFCRRRFCVIGCR? (SEQ ID NO: 38 );? ! !RGGKCVYCRXRFCVVCGR? (SEQ ID NO: 39 );? ! !RGGCKVYCRXRFCVIGCR? (SEQ ID NO: 40 );? ! !RATRCIFCrRRFCVVCGr? (SEQ ID NO: 41 );? ! !RATCRIFCrRRFCVVGCr? (SEQ ID NO: 42 );? ! !RGGKCVYCRxRFCVVCGR? (SEQ ID NO: 43 );? ! !RGGCKVYCRxRFCVVGCR? (SEQ ID NO: 44 );? ! !rggrclycrrrfcvvcgr? (SEQ ID NO: 45 );? ! !rggcrlycrrrfcvvgcr? (SEQ ID NO: 46 );? ! !rggrclycrrrfcivcg? (SEQ ID NO: 47 );? ! !rggcrlycrrrfcivgc? (SEQ ID NO: 48 );? ! !rgggclycrrrfcvvcgr? (SEQ ID NO: 49 );? ! !rggcglycrrrfcvvgcr? (SEQ ID NO: 50 );? ! !rggrclycrgwicfvcgr? (SEQ ID NO: 51 );? ! !rggcrlycrgwicfvgcr? (SEQ ID NO: 52 );? ! !RGGCLRYCRPRFCVRVCR? (SEQ ID NO: 53 );? ! !RGGCRLYCRRRFCVVGCR? (SEQ ID NO: 54 );? ! !RGVCLRYCRGRFCVRLCR? (SEQ ID NO: 55 );? ! !RGRVCLRYCRGRFCVRLCFR? (SEQ ID NO: 56 );? ! !RWRVCLRYCRGRFCVRLCLR? (SEQ ID NO: 57 );? ! !RGWRVCLKYCRGRFCVKLCLR? (SEQ ID NO: 58 );? ! !RGGRVCLRYCRGKFCVRLCLR? (SEQ ID NO: 59 );? ! !RGGRCLYARRRFAVVCGR? (SEQ ID NO: 6 O);? ! !RGGRCLYARRRFSIVC? (SEQ ID NO: 61 );? ! !RGGGCLYSRRRFAVVCGR? (SEQ ID NO: 62 );? ! !RGGRCLYARRRFGVVC? (SEQ ID NO: 63 );? ! !KGGRCLYVRRRFIVVC? (SEQ ID NO: 64 );? ! !RGGXCLYARRRFVGCV? (SEQ ID NO: 65 );? ! !RGGXCLYAXRRFSVVCR? (SEQ ID NO: 66 );? ! !RGGCXLYAXRRFSVVGCR? (SEQ ID NO: 67 );? ! !RGGRCVYVRXRFLVCVGR? (SEQ ID NO: 68 );? ! !RGGRCLYSRKKWAVSCGR? (SEQ ID NO: 69 );? ! !RGGRCLYSRXRYSVICGR? (SEQ ID NO: 70 );? ! !RGSGCIYCRRKWGVVGCR? (SEQ ID NO: 71 );? ! !RATRCIFSRRRFSVVCGR? (SEQ ID NO: 72 );? ! !RGGKCVYGRXRFSVVCGR? (SEQ ID NO: 73 );? ! !RATRCIFGrRRFGVVCGr? (SEQ ID NO: 74 );? ! !RGGKCVYLRXRFLVVCGR? (SEQ ID NO: 75 );? ! !RGGRCVFLRPRIGVVCGR? (SEQ ID NO: 76 );? ! !RGGCLRYAVPRFAVRVCR? (SEQ ID NO: 77 );? ! !RGGCLRYTKPKFTVRVCR? (SEQ ID NO: 78 );? ! !RGGCLRYAVGRFAVRVCR? (SEQ ID NO: 79 );? ! !RGGCLRYARZRFAVRVCR? (SEQ ID NO: 80 );? ! !RGFCLRYTVPRFTVRFCVR? (SEQ ID NO: 81 );? ! !RGFCLRYKVGRFKVRFCVR? (SEQ ID NO: 82 );? ! !RGFCLRYZVGRFZVRFCVR? (SEQ ID NO: 83 );? ! !RGGCLRYARZRFAVRVCR? (SEQ ID NO: 84 );? ! !RGGCLRYAVGRFAVRVCR? (SEQ ID NO: 85 );? ! !RGGRCLYCRRRFCVVGCR? (SEQ ID NO: 86 );? ! !RGGCRLYCRRRFCVCVGR? (SEQ ID NO: 87 );? ! !RGGRCLYCRRRFCVCVGR? (SEQ ID NO: 88 );? ! !RGGCRLYCRRRFCVCVGR? (SEQ ID NO: 89 );? ! !RGGRLCYCRRRFCVVCGR? (SEQ ID NO: 90 );? ! !RGGRLCYCRRRFCVVGCR? (SEQ ID NO: 91 );? ! !RGGCRLYCRRRFCVVGC? (SEQ ID NO: 92 );? ! !RGGRCLYCRRRFCVVGC? (SEQ ID NO: 93 );? ! !RGGCRLYCRRRFCVVCG? (SEQ ID NO: 94 );? ! !RGGRCLYCRRRFCVCVG? (SEQ ID NO: 95 );? ! !RGGCRLYCRRRFCVCVG? (SEQ ID NO: 96 );? ! !RGGRLCYCRRRFCVVCG? (SEQ ID NO: 97 );? ! !RGGRLCYCRRRFCVVGC? (SEQ ID NO: 98 );? ! !RGGGCLYCRRRFCVVGCR? (SEQ ID NO: 99 );? ! !RGGGCLYCRRRFCVCVGR? (SEQ ID NO: 100 );? ! !RGGCGLYCRRRFCVCVGR? (SEQ ID NO: 101 );? ! !RGGGLCYCRRRFCVVCGR? (SEQ ID NO: 102 );? ! !RGGGLCYCRRRFCVVGCR? (SEQ ID NO: 103 );? !
!
and the C-terminal amidated and N-terminal acylated forms thereof, wherein X is Har, x is D-Har, Z is MeGly and lower case letters represent D-amino acids.
30 . A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
31 . A method of inhibiting the growth of a microbe or the replication of a virus which comprises the step of contacting said virus or said microbe with an amount of a compound according to claim 1 effective to inhibit said growth or said replication.
32 . The method of claim 31 in which the microbe is a bacteria.
33 . The method of claim 32 in which the bacteria is selected from the group consisting of E. coli, L. monocytogenes, B. subtilis, S. typhimurium, S. aureus and P. aeruginosa.
34 . The method of claim 31 in which the microbe or virus is a sexually-transmitted microbe or virus.
35 . The method of claim 34 in which the sexually-transmitted microbe or virus is selected from the group consisting of HIV-1, C. trachomatis, T. pallidum, N. gonorrhoeae, T. vaginalis , HSV-1, HSV-2, H. ducreyi and human papilloma virus.
36 . The method of claim 31 in which the microbe or virus is HIV.
37 . The method of claim 31 in which the microbe or virus is methicillin-resistant S. aureus (MRSA) or vancomycin-resistant E. faecalis (VREF).
38 . A method to inactivate the endotoxin of gram-negative bacteria, which method comprises contacting said endotoxin with an amount of a compound according to claim 1 effective to inactivate said endotoxin.
39 . A method to treat or prevent a microbial or viral infection in a subject, which method comprises administering to a subject in need of such treatment an amount of a compound according to claim 1 effective to ameliorate said infection in the subject.
40 . The method of claim 39 in which the infection is a bacterial infection.
41 . The method of claim 40 in which the bacteria is selected from the group consisting of E. Coli, L. monocytogenes, B. subtilis, S. typhimurium, S. aureus and P. aeruginosa.
42 . The method of claim 39 in which the infection is caused by a sexually-transmitted pathogen.
43 . The method of claim 42 in which the sexually-transmitted pathogen is selected from the group consisting of HIV-1, C. trachomatis, T. pallidum, N. gonorrhoeae, T. vaginalis , HSV-1, HSV-2, H. ducreyi and human papilloma virus.
44 . The method of claim 39 in which the infection is an HIV infection.
45 . The method of claim 39 in which the infection is a methicillin-resistant S. aureus (MRSA) or vancomycin-resistant E. faecalis (VREF) infection.
46 . The method of claim 39 in which the compound is administered topically.
47 . The method of claim 39 in which the compound is administered prophylactically.Join the waitlist — get patent alerts
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