Inhibitors of fusion between viral and cell membranes as well as compositions and methods of using them
The present application relates to an inhibitor of fusion between a viral membrane from an enveloped virus and a cell membrane, where the viral membrane comprises a fusion mediating protein including a C-terminal peptide. The inhibitor comprises the C-terminal peptide of the fusion mediating protein from an enveloped virus and tocopherol or a derivative or pharmaceutically acceptable salt thereof attached to the C-terminal peptide. Also disclosed is a pharmaceutical composition including the inhibitor as well as methods of inhibiting viral fusion, blocking viral spread, and preventing or treating viral infection, with the inhibitor or pharmaceutical composition.
1. An inhibitor of fusion between a viral membrane from an enveloped virus and a cell membrane, wherein the viral membrane comprises a fusion mediating protein including a C-terminal peptide, said inhibitor comprising:
the C-terminal peptide of the fusion mediating protein from an enveloped virus and
tocopherol or a derivative or pharmaceutically acceptable salt thereof attached to the C-terminal peptide, wherein the C-terminal peptide is dimerized.
2. The inhibitor of claim 1 , wherein the C-terminal peptide is a Type I viral fusogenic peptide.
3. The inhibitor of claim 1 , wherein the C-terminal peptide is covalently or non-covalently bound to the tocopherol or derivative or pharmaceutically acceptable salt thereof.
4. The inhibitor of claim 1 further comprising:
a linker coupling the C-terminal peptide and the tocopherol or the derivative or pharmaceutically acceptable salt thereof.
5. The inhibitor of claim 4 , wherein the linker is selected from the group consisting of a peptide of two or more amino acids and one or more polyethylene glycol oligomer moieties.
6. The inhibitor of claim 5 , wherein the linker comprises one or more polyethylene glycol oligomer moieties having a formula of —(OCH 2 CH 2 ) m —, wherein m is an integer 1 to 24.
7. The inhibitor of claim 1 further comprising:
an immunogenic carrier molecule linked to the C-terminal peptide or to the tocopherol, tocopherol derivative, or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising:
the inhibitor of claim 1 and
an adjuvant.
9. The inhibitor of claim 1 further comprising:
a cell penetrating peptide linked to the C-terminal peptide, wherein the cell penetrating peptide is selected from the group consisting of YGRKKRRQRRR (SEQ ID NO: 2) and PFVYLI (SEQ ID NO: 3).
10. The inhibitor of claim 1 , wherein the C-terminal peptide is an HRC peptide.
11. The inhibitor of claim 10 , wherein the HRC peptide is derived from a virus selected from the group consisting of Measles virus, Ebola virus, Human parainfluenza virus, Nipah virus, and HIV-1.
12. The inhibitor of claim 11 , wherein the HRC peptide is derived from Measles virus and the inhibitor is selected from the group consisting of MV HRC5 and MV HRC6.
13. The inhibitor of claim 11 , wherein the HRC peptide is derived from Human parainfluenza virus and the inhibitor is VIKI-PEG4-tocopherol.
14. The inhibitor of claim 11 , wherein the HRC peptide is derived from Nipah virus and the inhibitor is VIKI-PEG4-tocopherol.
15. The inhibitor of claim 11 , wherein the HRC peptide is derived from Ebola virus and the inhibitor is TAT-Ebola-PEG4-toco.
16. The inhibitor of claim 1 , wherein the inhibitor includes tocopherol, wherein the tocopherol is selected from the group consisting of alpha-tocopherol, beta-tocopherol, gamma-tocopherol, and delta-tocopherol.
17. A method of inhibiting viral fusion in a subject comprising:
selecting a subject infected with or at risk of being infected with a virus and
administering to the selected subject the inhibitor of claim 1 under conditions effective to inhibit viral fusion.
18. A method of blocking measles viral spread in a subject comprising:
selecting a subject infected with or at risk of being infected with a measles virus and
administering to the selected subject the inhibitor of claim 1 under conditions effective to block measles viral spread.