Cholesterol derivatives of inhibitors of viral fusion
Inventors
Pessi, Antonello • Bianchi, Elisabetta • Ingallinella, Paolo
Assignees
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Publication Number
US-8629101-B2
Publication Date
2014-01-14
Expiration Date
Abstract
The present invention relates to compounds comprising at least ten contigous amino acids of the HR2 domain of a Type 1 viral fusogenic protein of an enveloped virus, or a derivative thereof, attached at the C-terminal to cholesterol or a derivative thereof; or a pharmaceutically acceptable salt thereof which inhibit viral fusion. Thus compounds of the invention are useful to prevent or treat diseases caused by an enveloped virus.
Core Innovation
The invention relates to cholesterol-anchored viral fusion inhibitors that comprise 10 or fewer contiguous amino acids from the HR2 domain of a Type 1 enveloped viral fusogenic protein. In preferred embodiments, the HR2/C34 region of HIV-1 gp41 is used, where the inhibitor functions as an inhibitor of viral fusion involving the viral six-helix bundle.
The HR2-derived peptide is attached at its C-terminus to a cholesterol moiety or a cholesterol derivative. The cholesterol attachment is performed directly or via a flexible linker, including PEG, and via a thioether attachment using a cysteine at the peptide C-terminus.
The document describes inhibiting fusion of enveloped viruses, including HIV-1 and AIDS, by targeting membrane/lipid rafts to improve antiviral activity. Cholesterol conjugation restores or increases antiviral potency, improves breadth across HIV-1 isolates, increases retention on target cells after wash, and improves pharmacokinetics, including detectable plasma levels and half-life in mice.
The document further describes potential formulation forms for the cholesterol-anchored inhibitors, including pessary, vaginal ring, cream, and gel, and discusses therapeutic use against enveloped viruses. It also references biological context involving lipid rafts/caveolae, including caveolin-1, and related mechanisms such as membrane-proximal external region features associated with viral fusion.
Claims Coverage
The patent’s independent claim is directed to an inhibitor of viral fusion, optionally as a pharmaceutically acceptable salt. The dependent claims refine the scope into pharmaceutical compositions and further narrow the dosage forms to pessary, vaginal ring, cream, or gel, yielding three layers of coverage built around the inventive inhibitor and its formulation.
Viral fusion inhibitor
An inhibitor of viral fusion, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the viral fusion inhibitor or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable excipient.
Topical/vaginal dosage forms
The pharmaceutical composition formulated as a pessary, vaginal ring, cream, or gel.
Overall, the claim set covers an inhibitor of viral fusion, extends coverage to pharmaceutical compositions including a pharmaceutically acceptable excipient, and narrows formulation scope to pessary, vaginal ring, cream, or gel.
Stated Advantages
Cholesterol conjugation restores or increases antiviral potency.
Improved breadth across HIV-1 isolates.
Improved retention on target cells after wash.
Improved pharmacokinetics, including increased detectable plasma level and half-life in mice.
Documented Applications
Therapeutic use as an inhibitor of viral fusion against enveloped viruses, including HIV-1 and AIDS.
Formulation for delivery as a pessary, vaginal ring, cream, or gel.
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