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- Title
A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry.
- Authors
Herschhorn, Alon; Gu, Christopher; Espy, Nicole; Richard, Jonathan; Finzi, Andrés; Sodroski, Joseph G
- 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.
- Subjects
HIV protease inhibitors; GLYCOPROTEINS; CD4 antigen; PROTEIN conformation; PROTEIN structure
- Publication
Nature Chemical Biology, 2014, Vol 10, Issue 10, p845
- ISSN
1552-4450
- Publication type
Article
- DOI
10.1038/nchembio.1623