HIV Small Molecule Fusion Inhibitors

Summary Viral fusion inhibitors represent the newest class of HIV drugs. Fuzeon (enfuvirtide), a synthetic peptide, is the first viral fusion inhibitor to be approved by the FDA, and works by interfering with crucial gp41 conformational changes in the HIV envelope that normally enable viral entry into host cells.

Using a novel protein-based screen designed to mimic the gp41 conformational change, the reseachers discovered a series of small molecules that prevent the formation of post-fusion gp41. To date, there have been no reports of small molecule HIV fusion inhibitors. One set of structurally related molecules inhibited formation of a postfusion-like assembly of gp120/gp41 with an IC50 of approximately 5 microM. The compounds also inhibited envelope-mediated membrane fusion in both cell-cell fusion and viral infectivity assays. Tested against a panel of envelope proteins from primary HIV-1 isolates, the compounds inhibited fusion across a broad range of clades, including both M and T tropic strains. Structurally, the compounds bound to a highly conserved, hydrophobic pocket on the inner core of the gp41 trimer, a region previously identified as a potential inhibitor site.

Applications The small molecules discovered by the screen show promise to inhibit HIV-1 viral fusion. Fuzeon is currently prescribed in combination with other anti-HIV medicines, in patients that show continuing viral load increases despite anti-viral treatment. Currently, patients using Fuzeon must perform injections twice daily. This is a significant adoption barrier that next generation fusion inhibitors, particularly those that are small molecules, will address. For Further Information Please Contact the Director of Business Development Katie Gordon Email: [email protected] Telephone: (617) 432-0920

Inventor(s): Harrison, Stephen C.

Type of Offer: Licensing



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