Compositions and methods related to inhibition of respiratory syncytial virus entry

Patent metadata

Field	Value
Publication number	US-10765754-B2
Application number	US-201615753950-A
Country	US
Kind code	B2
Filing date	Aug 26, 2016
Priority date	Aug 28, 2015
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

Disclosed herein are compositions and methods for inhibiting respiratory syncytial virus (RSV) entry into a host cell. Also provided herein are methods of identifying a peptide that interacts with the N-trimer of RSV F protein.

First claim

What is claimed is:

1. An isolated D-peptide comprising the amino acid sequence of SEQ ID NO:42, wherein the amino acids of the D-peptide have a D-configuration with the exception of glycine and the D-peptide is capable of interacting with the N-trimer groove of respiratory syncytial virus (RSV) F protein.

2. The isolated D-peptide of claim 1 , wherein the D-peptide is linked to an identical D-peptide.

3. The isolated D-peptide of claim 1 , wherein the D-peptide is linked to two identical D-peptides.

4. The isolated D-peptide of claim 1 , wherein the D-peptide comprises an amino acid sequence selected from any one of SEQ ID NOS:23-31, 122-124, 128-146, 214-216, 152, and 159.

5. The isolated D-peptide of claim 1 , wherein the N-terminus of the D-peptide is capped with an acetyl group.

6. The isolated D-peptide of claim 1 , wherein the C-terminus of the D-peptide is capped with an amide group.

7. An isolated composition comprising a first D-peptide comprising the amino acid sequence of SEQ ID NO:42, wherein the amino acids of the first D-peptide have a D-configuration with the exception of glycine and the first D-peptide is capable of interacting with the N-trimer groove of respiratory syncytial virus (RSV) F protein.

8. The isolated composition according to claim 7 , wherein the first D-peptide is linked to a second D-peptide, wherein the amino acids of the second D-peptide have a D-configuration with the exception of glycine.

9. The isolated composition according to claim 8 , wherein the second D-peptide is identical to the first D-peptide.

10. The isolated composition according to claim 7 , wherein the first D-peptide is linked to a second D-peptide and a third D-peptide, wherein the amino acids of the third D-peptide have a D-configuration with the exception of glycine.

11. The isolated composition according to claim 10 , wherein the first D-peptide, second D-peptide, and third D-peptide are identical.

12. The isolated composition according to claim 10 , wherein the first D-peptide, the second D-peptide, and the third D-peptide, are multimerized through a cross-linker.

13. The isolated composition of claim 12 , wherein the cross-linker is a polyethylene glycol (PEG) linker.

14. The isolated composition according to claim 12 , wherein the N-termini of the D-peptides are cross-linked.

15. The isolated composition according to claim 12 , wherein the C-termini of the D-peptides are cross-linked.

16. The isolated composition according to claim 12 , wherein the N-terminus or C-terminus of each D-peptide is cross-linked.

17. The isolated composition according to claim 12 , wherein the first D-peptide, the second D-peptide, and the third D-peptide, are multimerized through a scaffold having the following structure:

18. The isolated composition according to claim 17 , wherein:
the N-termini of the D-peptides are attached to the scaffold;
the C-termini of the D-peptides are attached to the scaffold; or
the N-terminus or C-terminus of each D-peptide is attached to the scaffold.

19. The isolated composition of claim 7 , wherein the first D-peptide comprises an amino acid sequence selected from any one of SEQ ID NOS:23-31, 122-124, 128-146, 214-216, 152, and 159.

20. The isolated composition of claim 19 , wherein the N-terminus of the D-peptide is capped with an acetyl group.

21. The isolated composition of claim 19 , wherein the C-terminus of the D-peptide is capped with an amide group.

22. The isolated composition of claim 17 , wherein:
the first, second, and third D-peptide each comprises the amino acid sequence of Ac-K(PEG4)-DDG-GECVNRPEWLLDWCGT-NH2 (SEQ ID NO:142); or
the first, second, and third D-peptide each comprises the amino acid sequence of Ac-K(PEG4)-EEG-GECVNRPEWLLDWCGT-NH2 (SEQ ID NO:214).

23. The isolated composition of claim 7 , wherein the first D-peptide is linked to a potency enhancing cargo molecule.

24. The isolated composition of claim 23 , wherein the potency enhancing cargo molecule is a cholesterol, sterol, sugar, maltose binding protein, ubiquitin, streptavidin, immunoglobulin domain, keyhole limpet hemacyanin, sperm whale myoovalbumin, bovine pancreatic trypsin inhibitor, green fluorescent protein, gold particle, magnetic particle, agarose bead, lactose bead, fatty acid, a high molecular weight PEG, or serum albumin.

25. The isolated composition of claim 23 , wherein the potency enhancing cargo molecule is linked to the first D-peptide with a PEG linker.

26. The isolated composition according to claim 10 , wherein a trimer of the first, second, and third D-peptides exhibits enhanced binding affinity or anti-viral activity as compared with the binding affinity or anti-viral activity of an isolated composition comprising the first D-peptide as a monomer.

27. The isolated composition according to claim 10 , wherein the composition further comprises a pharmaceutically acceptable carrier.

28. A method for inhibiting entry of respiratory syncytial virus (RSV) into a host cell, comprising exposing the RSV virus to the D-peptide of claim 1 , thereby inhibiting entry of the virus into the host cell.

29. The method according to claim 28 , wherein the D-peptide comprises an amino acid sequence as set forth in SEQ ID NO:142 or SEQ ID NO:214.

30. A method for inhibiting entry of RSV into a host cell, comprising exposing the RSV virus to a composition comprising a first D-peptide, a second D-peptide, and a third D-peptide that are multimerized through a scaffold having the following structure:

wherein each of the first, second, and third D-peptides comprises an amino acid sequence as set forth in SEQ ID NO:142; or each of the first, second, and third D-peptides comprises an amino acid sequence as set forth in SEQ ID NO:214; and wherein the amino acids of the first, second, and third D-peptides have a D-configuration with the exception of glycine.

31. A method of treating respiratory syncytial virus (RSV) infection in a subject, comprising administering to the subject a therapeutically effective amount of the D-peptide of claim 1 .

32. A method of treating RSV infection in a subject, comprising administering to the subject a therapeutically effective amount of a D-peptide according to claim 4 .

33. A method of treating RSV infection in a subject comprising administering to the subject a therapeutically effective amount of a composition according to claim 22 .

34. The method of claim 31 , wherein the D-peptide w is administered concurrently or sequentially with at least one additional anti-viral agent.

35. The method of claim 34 , wherein the at least one additional anti-viral agent is a viral fusion inhibitor, viral attachment inhibitor, viral replication inhibitor, a viral protease inhibitor, an inhibitor antibody, a biologic, an antisense molecule, an RNA interference agent, a peptide, or a small molecule.

36. The isolated D-peptide of claim 1 , wherein the D-peptide is 8 to 30 amino acids in length.

Assignees

• Navigen Inc
• Univ Utah Res Found

Inventors

• Welch Brett D
• Kay Michael S
• Eckert Debra Muir
• Mckinnon Rena
• Jacobsen Michael Thomas

Classifications

• A61K38/162 Primary

  from virus · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/10

  Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K38/02

  Peptides of undefined number of amino acids; Derivatives thereof · CPC title