TY - JOUR
T1 - A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry
AU - Herschhorn, Alon
AU - Gu, Christopher
AU - Espy, Nicole
AU - Richard, Jonathan
AU - Finzi, Andrés
AU - Sodroski, Joseph G.
N1 - Publisher Copyright:
© 2014 Nature America, Inc. All rights reserved.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - 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.
AB - 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.
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U2 - 10.1038/nchembio.1623
DO - 10.1038/nchembio.1623
M3 - Article
C2 - 25174000
AN - SCOPUS:84922062993
SN - 1552-4450
VL - 10
SP - 845
EP - 852
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 10
ER -