USRE38828EExpiredUtility
Parevins and tachytegrins
Est. expiryJul 6, 2015(expired)· nominal 20-yr term from priority
A61L 12/14A01N 37/46C07K 7/08A61K 38/00
58
PatentIndex Score
2
Cited by
35
References
22
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-modified1. An antimicrobial 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, 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 a thiol-containing amino acid, 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 a thiol-containing amino acid, a basic amino acid, a hydrophobic amino acid, a polar/large amino acid and a small amino acid;
each of C 8 and C 13 is independently a thiol-containing amino acid;
each of C 6 and C 15 is independently selected from the group consisting of a thiol-containing amino acid, 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 a thiol-containing amino acid, 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 a thiol-containing amino acid, the other two are other than a thiol-containing amino acid;
(ii) when one of C 15 , C 16 or C 17 is a thiol-containing amino acid, the other two are other than a thiol-containing amino acid;
and (iii) the compound has one feature selected from the group consisting of:
(1) C 4 and C 15 are each independently a thiol-containing amino acid;
(2) C 4 and C 16 are each independently a thiol-containing amino acid;
(3) C 4 and C 17 are each independently a thiol-containing amino acid;
(4) C 5 and C 15 are each independently a thiol-containing amino acid;
(5) C 5 and C 16 are each independently a thiol-containing amino acid;
(6) C 6 and C 16 are each independently a thiol-containing amino acid; and
(7) C 6 and C 17 are each independently a thiol-containing amino acid.
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 -C16 and the other links C 8 -C 13 .
4. The compound of claim 2 , wherein one of said disulfide bridges links C 5 -C 8 and the other links C 13 -C 16 .
5. The compound of claim 2 , wherein one of said disulfide bridges links C 4 -C 17 and the other links C 8 -C 13 .
6. The compound of claim 1 in which at least one of A 1 , A 2 or A 3 is not present.
7. The compound claim 1 in which A 1 , A 2 and A 3 are not present.
8. The compound of claim 1 in which at least one of A 1 , A 2 or A 3 is a hydrophobic amino acid.
9. 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.
10. 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.
11. 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.
12. 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.
13. The compound of claim 1 in which all amino acids are in the D-configuration.
14. The compound of claim 1 in which A 7 and A 14 are each independently a hydrophobic amino acid.
15. The compound of claim 1 in which A 9 or A 12 is a hydrophobic amino acid or a small amino acid.
16. 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.
17. The compound of claim 1 in which A 9 -A 10 -A 11 -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-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.
18. The compound of claim 1 which is selected from the group consisting of:
RGGRCLYCRRRFCVVCGR (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); XGGRCLYCRRRFCVVCG (SEQ ID NO: 23); XGGCRIYCRRRFCVIGC (SEQ ID NO: 24); RGGXCLYCRRRFCVVC (SEQ ID NO: 25); RGGCXLYCRRRFCVIC (SEQ ID NO: 26); RGGXCLCXRRFCVVCGR (SEQ ID NO: 27); RGGCXLCXRRFCVIGCR (SEQ ID NO: 28); RGGRCVYCRXRFCVVCGR (SEQ ID NO: 29); RGGCRVYCRXRFCVVGCR (SEQ ID NO: 30); RGGRCLYCRKXWCVVCGR (SEQ ID NO: 31); RGGCRLYCRKKWCVVGCR (SEQ ID NO: 32); RGGRCLYCRXRYCVVCGR (SEQ ID NO: 33); RGGCRLYCRXRYCVVACR (SEQ ID NO: 34); RGSGCLYCRRXWCVVCGR (SEQ ID NO: 35); RGSCGLYCRRXWCVVGCR (SEQ ID NO: 36); RATRCIFCRRRFCVVCGR (SEQ ID NO: 37); RATCRIFCRRRFCVIGCR (SEQ ID NO: 38); RGGKCVYCRXRFCVVCGR (SEQ ID NO: 39); RGGCKVYCRXRFCVIGCR (SEQ ID NO: 40); RATRIFCrRRFCVVCGr (SEQ ID NO: 41); RATCRIFCrRRFCVVGCr (SEQ ID NO: 42); RGGKCVYCRxRFCVVCGR (SEQ ID NO: 43); RGGCXVYCRxRFCVVGCR (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); RGVLRYCRGRFCVRLCR (SEQ ID NO: 55); RGRVCLRYCRGRFCVRLCFR (SEQ ID NO: 56); RWRVCLRYCRGRFCVRLCLR (SEQ ID NO: 57); RGWRVCLKYCRGRFCVKLCLR (SEQ ID NO: 58); RGGRVCLRYCRGKFCVRLCLR (SEQ ID NO: 59); RGGCLYARRRFAVVCGR (SEQ ID NO: 60); RGGRCLYARRRFSIYC (SEQ ID NO: 61); RGGGCLYSRRRFAVVCGR (SEQ ID NO: 62); RGGRCLYARRRFGVVC (SEQ ID NO: 63); KGGRCLYVRRRFIVVC (SEQ ID NO: 64); RGGXCLYARRRFVGCV (SEQ ID NO: 65); RGGXCLYAXRRFSVVCGR (SEQ ID NO: 66); RGGCXLYAXRRFSVVGCR (SEQ ID NO: 67); RGGRCVYVRXRFLVCVGR (SEQ ID NO: 68); RGGRCLYSRXXWAVSCGR (SEQ ID NO: 69); RGGRCLYSRXRYSVICGR (SEQ ID NO: 70); RATRCIFSRRRFSVVCGR (SEQ ID NO: 72); RGGXCVYGRXRFSVVCGR (SEQ ID NO: 73); RATRCIFGrRRFGVVCGr (SEQ ID NO: 74); RGGXCVYLRxRFLVVCGR (SEQ ID NO: 75); RGGRCVFLRPRIGVVCGR (SEQ ID NO: 76); RGGCLRYAVPRFAVRVCR (SEQ ID NO: 77); RGGCLRYTKPXFTRVCR (SEQ ID NO: 78); RGGCLRYAVGRFAVRVCR (SEQ ID NO: 79); RGGCLRYARZRFAVRVCR (SEQ ID NO: 80); RGFCLRYTVPRFTVRFCVR (SEQ ID NO: 81); RGRCLRYKVGRFXRFCVR (SEQ ID NO: 82); RGFCLRYZVGRFZVRFCVR (SEQ ID NO: 83); RGGCLRYARZRFAVRVCR (SEQ ID NO: 84); RGGCLRYAVGRFAVRVCR (SEQ ID NO: 85); RGGCRLCRRRFCVVCGR (SEQ ID NO: 87); RGGRCLYCRRFCVCVGR (SEQ ID NO: 88); RGGCRLYCRRRFCVCVGR (SEQ ID NO: 89); RGGRLCYCRRRFCVVGCR (SEQ ID NO: 90); RGGRLCYCRRRFCVVGCR (SEQ ID NO: 91); RGGRLCYCRRRFCVVGC (SEQ ID NO: 92); 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); 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.
19. The compound of claim 3 which is selected from the group consisting of:
RGGRRCLYCRRRFCVVCGR (SEQ ID NO: 1); RGGRCLYCRRRFCIVCG (SEQ ID NO: 13); RGGCCLYCRRRFCVVCGR (SEQ ID NO: 3); RGGRCLYCRGWICFVCGR (SEQ ID NO: 4); RGGRCLYCRPRFCVVCGR (SEQ ID NO: 5); RGGRCVYCRRRFCVVCG (SEQ ID NO: 21); XGGRCLYCRRRFCVVCG (SEQ ID NO: 23); RGGXCLYCRRRFCVVC (SEQ ID NO: 25); RGGXCLYCXRRFCVVCGR (SEQ ID NO: 27); RGGRCVYCRXRFCVVCGR (SEQ ID NO: 29); RGGRCLYCRXXWCVVCGR (SEQ ID NO: 31); RGGRCLCRXRYCVVCGR (SEQ ID NO: 33); RGSGCLYCRRKWCVVCGR (SEQ ID NO: 35); RATRCIFCRRRFCVVCGR (SEQ ID NO: 37); RGGKCVYCRXRFCVVCGR (SEQ ID NO: 39); RATRCIFCrRRFCVVCGr (SEQ ID NO: 41); RGGXCVYCRxRFCVVCGR (SEQ ID NO: 43); rggrclycrrrfcvvcgr (SEQ ID NO: 45); rggrclycrrrfcivcg (SEQ ID NO: 47); rgggclycrrrfcvvcgr (SEQ ID NO: 49); rggrclycrgwicfvcgr (SEQ ID NO: 51); RGGRCLYCRRRFCIVCGR (SEQ ID NO: 2);
and the C-terminal amidated forms thereof, wherein X is Har, x is D-Har and lower case letters represent D-amino acids.
20. The compound of claim 4 which is selected from the group consisting of:
RGGRCLYCRRRFCVVCGR (SEQ ID NO: 1); RGGRCLYCRRRFCIVCG (SEQ ID NO: 13); RGGGCLYCRRRFCVVCGR (SEQ ID NO: 3); RGGRCLYCRGWICFVCGR (SEQ ID NO: 4); RGGRCLYCRPRFCVVCGR (SEQ ID NO: 5); RGGRCVYCRRRFCVVCG (SEQ ID NO: 21); XGGRCLYCRRRFCVVCG (SEQ ID NO: 23); RGGXCLYCRRRFCVVC (SEQ ID NO: 25); RGGXCLYCXRRFCVVCGR (SEQ ID NO: 27); RGGRCVYCRXRFCVVCGR (SEQ ID NO: 29); RGGRCLYCRXXWCVCGR (SEQ ID NO: 31); RGGRCLYCRXRYCVVCGR (SEQ ID NO: 33); RGSGCLYCRRXWCVVCGR (SEQ ID NO: 35); RATRCIFCRRRFCVVCGR (SEQ ID NO: 37); RGGKCVYCRXRFCVVCGR (SEQ ID NO: 39); RATRCIFCrRRFCVVCGr (SEQ ID NO: 41); RGGXCVYCRxRFCVVCGR (SEQ ID NO: 43); rggrclycrrrfcvvcgr (SEQ ID NO: 45); rggrclycrrrfcivcg (SEQ ID NO: 47); rgggclycrrrfcvvcgr (SEQ ID NO: 49); rggrclycrgwicfvcgr (SEQ ID NO: 51); RGGRCLYCRRRFCIVCGR (SEQ ID NO: 2);
and the C-terminal amidated forms thereof, wherein X is Har, x is D-Har and lower case letters represent D-amino acids.
21. The compound of claim 5 which is selected from the group consisting of:
RGGCRLYCRRRFCVVGCR (SEQ ID NO: 12); RGGCRLYCRRRFCIVGCR (SEQ ID NO: 7); RGGCGLYCRRRFCVVGCR (SEQ ID NO: 16); RGGCRLYCRGWICFVGCR (SEQ ID NO: 18); RGGCRLYCRPRFCVVGCR (SEQ ID NO: 20); RGGCRVYCRRRFCVIGC (SEQ ID NO: 22); XGGCRIYCRRRFCVIGC (SEQ ID NO: 24); RGGCXLYCXRRFCVIGCR (SEQ ID NO: 28); RGGCRVYCRXRFCVVGCR (SEQ ID NO: 30); RGGCRLYCRXXWCVVGCR (SEQ ID NO: 32); RGGCRLYCRXRYCVVACR (SEQ ID NO: 34); RGSCGLYCRRXWCVVGCR (SEQ ID NO: 36); RATCRIFCRRRFCVIGCR (SEQ ID NO: 38); RGGCKVYCRXRFCVIGCR (SEQ ID NO: 40); RATCRIFCrRRFCVVGCr (SEQ ID NO: 42); RGGCXVYCRxRFCVVGCR (SEQ ID NO: 44); rggcrlycrrrfcvvgcr (SEQ ID NO: 46); rggcrlycrrrfcivgc (SEQ ID NO: 48); rggcrlycrgwicfvgcr (SEQ ID NO: 52); RGGCLRYCRPRFCVRVCR (SEQ ID NO: 53); RGVCLRYCRGRFCVRLCR (SEQ ID NO: 55); RGRVCLRYCRGRFCVRLCFR (SEQ ID NO: 56); RWRVCLRYGRFCVRLCLR (SEQ ID NO: 57); RGWRVCLKYCRGRFCVRLCLR (SEQ ID NO: 58); RGGRVCLRYCRGXFCVRLCLR (SEQ ID NO: 59); RGGCRLYCRRRFCVVGC (SEQ ID NO: 92); RGGCRLYCRRRFCIVGC (SEQ ID NO: 14); rggcglycrrrfcvvgcr (SEQ ID NO: 50);
and the C-terminal amidated forms thereof, wherein X is Har, x is D-Har and lower case letters represent D-amino acids.
22. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.Cited by (0)
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