A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry

Alon Herschhorn, Christopher Gu, Nicole Espy, Jonathan Richard, Andrés Finzi, Joseph G. Sodroski

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Binding to the primary receptor, CD4, triggers conformational changes in the metastable HIV-1 envelope glycoprotein (Env) trimer ((gp120-gp41) 3) that are important for virus entry into host cells. These changes include an 'opening' of the trimer, creation of a binding site for the CCR5 co-receptor and formation and/or exposure of a gp41 coiled coil. Here we identify a new compound, 18A (1), that specifically inhibits the entry of a wide range of HIV-1 isolates. 18A does not interfere with CD4 or CCR5 binding, but it inhibits the CD4-induced disruption of quaternary structures at the trimer apex and the exposure of the gp41 HR1 coiled coil. Analysis of HIV-1 variants with increased or reduced sensitivity to 18A suggests that the inhibitor can distinguish distinct conformational states of gp120 in the unliganded Env trimer. The broad-range activity and observed hypersensitivity of resistant mutants to antibody neutralization support further investigation of 18A.

Original languageEnglish (US)
Pages (from-to)845-852
Number of pages8
JournalNature Chemical Biology
Volume10
Issue number10
DOIs
StatePublished - Oct 1 2014

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