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• W2022689407 abstract "Fusion inhibitors are a relatively new class of antiretroviral drugs that block conformational changes in the HIV envelope glycoprotein (Env) critical for virus-cell fusion. Proof-of-concept for this therapeutic approach is provided by enfuvirtide, a peptide that inhibits terminal conformational changes in gp41. The identification of non-peptide, orally bioavailable fusion inhibitors may provide valuable new therapeutic options for people living with HIV/AIDS. Using a cell-based assay for inhibition of critical Env conformational changes we identified three structurally distinct series of drug-like small molecule fusion inhibitors (median MW ∼470; cLogP ∼4.3). The most potent compounds inhibited HIV-1 (but not HIV-2 or SIV) infection with an IC50 of approximately 5 nM and retained activity against X4 or R5 primary isolates from clades A, B, C, D, F, G, H, and group O. These compounds exhibited oral bioavailability of up to 30% in animal models. Unlike enfuvirtide, these compounds bind to Env prior to CD4 binding and stabilize gp120-gp41 association. Binding of these compounds unmasks conserved neutralization epitopes on Env. The compounds specifically block receptor-induced conformational changes that occur after exposure of the gp120 coreceptor binding site, but before exposure of the gp41 intermediate to which enfuvirtide binds. In vitro experiments indicate that these fusion inhibitors act synergistically with neutralizing antibodies, thereby enhancing their inhibitory potential. In vitro resistance determinants map to conserved regions in both gp120 and gp41. We have discovered a novel class of potent, orally bioavailable HIV-1 fusion inhibitors with a unique mechanism of action and resistance profile. Optimized lead compounds are currently in pre-clinical drug development. These compounds may also have promising applications in Env structural studies." @default.
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• W2022689407 date "2009-06-01" @default.
• W2022689407 modified "2023-09-27" @default.
• W2022689407 title "211 Potent Orally Bioavailable HIV-1 Fusion Inhibitors Alter Env Conformation and Expose Conserved Neutralization Epitopes" @default.
• W2022689407 doi "https://doi.org/10.1097/01.qai.0000351167.10725.ca" @default.
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