D-peptide inhibitors of HIV entry and methods of use

Patent metadata

Field	Value
Publication number	US-10487121-B2
Application number	US-201716068306-A
Country	US
Kind code	B2
Filing date	Jan 6, 2017
Priority date	Jan 7, 2016
Publication date	Nov 26, 2019
Grant date	Nov 26, 2019

Abstract

Disclosed are D-peptide compositions and methods for inhibiting HIV entry into host cells.

First claim

The invention claimed is:

1. A composition comprising at least one PIE12-2 D-peptide comprising SEQ ID NO:3 [Ac-HPCDYPEWQWLCELG-(PEG 4 )-K—NH 2 ], wherein the at least one PIE12-2 D-peptide interacts with the N-trimer pocket of HIV gp41.

2. The composition of claim 1 , comprising at least two PIE12-2 D-peptides comprising SEQ ID NO:3 [Ac-HPCDYPEWQWLCELG-(PEG 4 )-K—NH 2 ].

3. The composition of claim 1 , comprising at least three PIE12-2 D-peptides comprising SEQ ID NO:3 [Ac-HPCDYPEWQWLCELG-(PEG 4 )-K—NH 2 ].

4. The composition of claim 3 comprising three PIE12-2 D-peptides, wherein each PIE12-2 D-peptide is linked to an arm of a multimer scaffold comprising three arms via an amide bond between the epsilon amino group of the C-terminal D-lysine of the PIE12-2 D-peptide and a carboxyl group of the arm of the multimer scaffold, wherein the multimer scaffold is based on 4-Amino-4-(2-carboxyethyl)heptanedioic acid.

5. The composition of claim 4 , wherein each PIE12-2 D-peptide and linkage to the multimer scaffold is as shown in FIG. 4B .

6. The composition of claim 4 , wherein the multimer scaffold further comprises a fourth arm linking a cholesterol moiety via a polyethylene glycol (PEG) linker to the multimer scaffold, wherein the total number of ethylene glycol repeats in the fourth arm ranges from 12-132, and optionally wherein the cholesterol moiety is linked to the PEG linker via a carbamate linkage.

7. The composition of claim 6 , wherein the PEG linker comprises a first PEG chain and a second PEG chain linked in series linking the cholesterol moiety to the multimer scaffold.

8. The composition of claim 7 , wherein the total number of ethylene glycol repeats in the fourth arm is 32 and the first PEG chain comprises 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 ethylene glycol repeats and the second PEG chain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 ethylene glycol repeats, respectively.

9. The composition of claim 6 , wherein the PEG linker is linked to the multimer scaffold via an amide bond.

10. The composition of claim 7 , wherein the second PEG chain is linked to the first PEG chain via an amide bond.

11. The composition of claim 6 , wherein the cholesterol moiety is cholesteryl chloroformate.

12. The composition of claim 7 , wherein the first PEG chain is linked to the multimer scaffold prior to linking of the cholesterol moiety and second PEG chain, and the composition is optionally purified prior to linking of the cholesterol moiety and second PEG chain.

13. The composition of claim 6 , wherein addition of the cholesterol moiety to the fourth arm does not create stereoisomers.

14. The composition of claim 7 , wherein the cholesterol moiety is attached to the fourth arm of the multimer scaffold via the second PEG chain and is cholesteryl-PEG4-NHS ester as shown in the following figure:

15. The composition of claim 6 , comprising at least one trimeric PIE12-2 D-peptide-cholesterol conjugate having the following structure:

16. A pharmaceutical composition comprising a composition of claim 1 and a pharmaceutically acceptable carrier.

17. The composition of claim 1 , further comprising at least one anti-viral agent selected from a viral replication inhibitor, a viral protease inhibitor, a viral reverse transcriptase inhibitor, a viral entry inhibitor, a viral integrase inhibitor, a viral Rev inhibitor, a viral Tat inhibitor, a viral Nef inhibitor, a viral Vpr inhibitor, a viral Vpu inhibitor, and a viral Vif inhibitor.

18. A method of inhibiting HIV entry into a host cell comprising exposing the virus to a composition of claim 1 , thereby inhibiting HIV entry into the host cell.

19. A method of treating HIV infection in a subject comprising administering to the subject an effective amount of a composition of claim 1 , thereby treating HIV infection.

20. A method of synthesizing a trimeric D-peptide-cholesterol conjugate of the following structure,

wherein the method comprises the steps as set forth in FIG. 6 .

21. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is a depot formulation.

Assignees

• Navigen Inc
• Univ Utah Res Found

Inventors

• Welch Brett D
• Francis James Nicholas
• Kay Michael S

Classifications

• A61K47/554

  the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K38/08

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

• A61K47/542

  Carboxylic acids, e.g. a fatty acid or an amino acid · CPC title

• C07K14/162 Primary

  env, e.g. gp160, gp110/120, gp41, V3, peptid T, CD4-Binding site · CPC title