Methods and compositions related to inhibition of viral entry

1. A method for inhibiting human immunodeficiency virus (HIV) entry into a cell comprising exposing HIV to a composition comprising:

at least three D-peptides and at least one potency-enhancing cargo molecule linked to a tetrameric scaffold, wherein:

each D-peptide comprises the sequence of SEQ ID NO:37 (CDYPEWQWLC); and the potency-enhancing cargo molecule is a membrane localizing potency enhancing cargo molecule selected from the group consisting of a cholesterol or an analog thereof, alkane chain, and a fatty acid, and the membrane localizing potency-enhancing cargo molecule is linked to the tetrameric scaffold via a polyethylene glycol (PEG) linker comprising 12 to 132 PEG units

thereby inhibiting HIV entry into the cell.

2. A method of treating HIV infection in a subject comprising administering to the subject an effective amount of a composition comprising:

at least three D-peptides and at least one potency-enhancing cargo molecule linked to a tetrameric scaffold, wherein:

each D-peptide comprises the sequence of SEQ ID NO:37 (CDYPEWQWLC); and the potency-enhancing cargo molecule is a membrane localizing potency enhancing cargo molecule selected from the group consisting of a cholesterol or an analog thereof, alkane chain, and a fatty acid, and the membrane localizing potency-enhancing cargo molecule is linked to the tetrameric scaffold via a polyethylene glycol (PEG) linker comprising 12 to 132 PEG units.

3. The method of claim 2 , wherein the potency-enhancing cargo molecule is cholesterol or thiocholesterol.

4. The method of claim 2 , wherein the potency-enhancing cargo molecule is an alkane chain.

5. The method of claim 4 , wherein the potency-enhancing cargo molecule is a C8 alkane, a C16 alkane, or a C18 alkane.

6. The method of claim 2 , wherein the potency-enhancing cargo molecule is a fatty acid.

7. The method of claim 6 , wherein the potency-enhancing cargo molecule is a C8 fatty acid, a C16 fatty acid, or a C18 fatty acid.

8. The method of claim 2 , wherein each D-peptide is identical.

9. The method of claim 2 , wherein at least two D-peptides are different.

10. The method of claim 2 , wherein at least one D-peptide comprises the amino acid sequence of any one of SEQ ID NOS:6 and 23-29.

11. The method of claim 2 , wherein each D-peptide comprises an amino acid sequence of SEQ ID NO:26.

12. The method of claim 2 , wherein the tetrameric scaffold is a heterotetrameric scaffold comprising three NHS ester groups and a fourth orthogonal group, wherein the at least three D-peptides are linked to the heterotetrameric scaffold via the three NHS ester groups and the potency-enhancing cargo molecule is linked to the heterotetrameric scaffold via the fourth orthogonal group, wherein the fourth orthogonal group comprises the PEG linker comprising 12 to 132 PEG units.

13. The method of claim 2 , wherein the PEG linker is PEG12, PEG16, PEG24, PEG25, PEG26, PEG27, PEG28, PEG29, PEG30, PEG31, PEG32, PEG33, PEG34, PEG35, PEG36, PEG57 or PEG132.

14. The method of claim 2 , wherein the tetrameric scaffold comprises a tris, di-lysine, benzene ring, phosphate, or peptide core.

15. The method of claim 12 , wherein the potency enhancing cargo molecule is joined to the PEG linker via a reactive group.

16. The method of claim 15 , wherein the reactive group is a maleimide reactive group.

17. The method of claim 12 , wherein the tetrameric scaffold comprises a structure as follows:

18. The method of claim 2 , wherein the composition further comprises a pharmaceutically acceptable carrier.

19. The method of claim 2 , further comprising administering to the subject an antiviral agent or agents selected from the group consisting of 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.