Active cores of peptide triazole HIV-1 entry inhibitors
View Patent ↗The invention provides a peptide triazole conjugate and derivatives thereof, and methods of its use. Further provided are an antibody to the peptide triazole conjugate, and a method of identifying an HIV-1 entry inhibitor candidate.
1. A peptide triazole conjugate comprising a peptide component comprising the sequence X 1 X 2 X 3 NIPWX 4 (SEQ ID No. 3),
wherein X 1 is absent or E, wherein
X 2 is F, K, E, R and Cit;
wherein X 3 is N or I;
wherein X 4 is S or T;
wherein the proline in SEQ ID No. 3 is modified according to Formula I:
wherein R is a bulky aromatic group.
2. The peptide triazole conjugate of claim 1 , wherein the bulky aromatic group is selected from the group consisting of a naphthyl group; a para-alkyl-substituted phenyl, wherein the alkyl is methyl or ethyl; 2-phenylethyl; and a metallocene.
3. The peptide triazole conjugate of claim 1 , wherein the bulky aromatic group is a metallocene.
4. The peptide triazole conjugate of claim 3 , wherein the metallocene is ferrocene.
5. The peptide triazole conjugate of claim 1 , wherein X 3 is N.
6. The peptide triazole conjugate of claim 1 , wherein the sequence X 1 X 2 X 3 NIPWX 4 of the peptide triazole conjugate is a sequence selected from the group consisting of: SEQ ID No. 6, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 12.
7. A pharmaceutical composition comprising the peptide triazole conjugate of claim 1 and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition of claim 7 , wherein the bulky aromatic group of the peptide triazole conjugate is selected from the group consisting of a naphthyl group; a para-alkyl-substituted phenyl, wherein the alkyl is methyl or ethyl; 2-phenylethyl; and a metallocene.
9. The pharmaceutical composition of 7 , wherein R of the peptide triazole conjugate is ferrocene.
10. The pharmaceutical composition of claim 7 , wherein the sequence X 1 X 2 X 3 NIPWX 4 of the peptide triazole conjugate is a sequence selected from the group consisting of: SEQ ID No. 6, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 12.
11. A pharmaceutical composition comprising the peptide triazole conjugate of claim 1 , cyanovirin-N or a functional derivative thereof, and a pharmaceutically acceptable carrier.
12. The pharmaceutical composition of claim 11 , wherein the bulky aromatic group of the peptide triazole conjugate is selected from the group consisting of a naphthyl group; a para-alkyl-substituted phenyl, wherein the alkyl is methyl or ethyl; 2-phenylethyl; and a metallocene.
13. The pharmaceutical composition of claim 12 , wherein the peptide triazole conjugate is linked to the cyanovirin-N or a functional derivative thereof.
14. The pharmaceutical composition of claim 11 , wherein the N-terminal residue of the peptide triazole conjugate is covalently linked to the C-terminal residue of the cyanovirin-N or functional derivative thereof.
15. The pharmaceutical composition of claim 11 , formulated for topical or parenteral administration.
16. The pharmaceutical composition of claim 11 , wherein R of the peptide triazole conjugate is ferrocene.
17. The pharmaceutical composition of claim 11 , wherein the sequence X 1 X 2 X 3 NIPWX 4 of the peptide triazole conjugate is a sequence selected from the group consisting of: SEQ ID No. 6, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 12.
18. A method of treating HIV infection in an HIV-infected individual, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of claim 7 .
19. The method of claim 18 , wherein the bulky aromatic group of the peptide triazole conjugate is selected from the group consisting of a naphthyl group; a para-alkyl-substituted phenyl, wherein the alkyl is methyl or ethyl; 2-phenylethyl; and a metallocene.
20. The method of claim 18 , wherein the bulky aromatic group of the peptide triazole conjugate is a metallocene.
21. The method of claim 20 , wherein the metallocene of the peptide triazole conjugate is ferrocene.
22. The method of claim 18 , wherein the pharmaceutical composition further comprises cyanovirin-N or a functional derivative thereof.
23. The method of claim 18 , wherein the sequence X 1 X 2 X 3 NIPWX 4 of the peptide triazole conjugate is a sequence selected from the group consisting of: SEQ ID No. 6, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 12.
24. A method of reducing HIV infectivity in an individual, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of claim 7 .
25. The method of claim 24 , wherein the bulky aromatic group of the peptide triazole conjugate is selected from the group consisting of a naphthyl group; a para-alkyl-substituted phenyl, wherein the alkyl is methyl or ethyl; 2-phenylethyl; and a metallocene.
26. The method of claim 24 , wherein the bulky aromatic group of the peptide triazole conjugate is a metallocene.
27. The method of claim 26 , wherein the metallocene of the peptide triazole conjugate is ferrocene.
28. The method of claim 24 , wherein the pharmaceutical composition further comprises cyanovirin-N or a functional derivative thereof.
29. The method of claim 24 , wherein the administration is one of topical and parenteral.
30. The method of claim 24 , wherein the sequence X 1 X 2 X 3 NIPWX 4 of the peptide triazole conjugate is a sequence selected from the group consisting of: SEQ ID No. 6, SEQ ID No. 8, SEQ ID No. 9, SEQ ID No. 10, SEQ ID No. 11, and SEQ ID No. 12.
31. A method of isolating a viral envelope protein gp120 from a sample, the method comprising contacting sample comprising gp120 with the peptide triazole conjugate of claim 1 linked to a solid phase matrix, wherein:
the gp120 binds to the peptide triazole conjugate thereby partitioning the sample into a bound phase and an unbound phase; and
separating the unbound phase from the bound phase, thereby isolating the gp120 from the sample.