期刊
NATURE CHEMICAL BIOLOGY
卷 10, 期 10, 页码 845-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1623
关键词
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资金
- amfAR
- amfAR Mathilde Krim Fellowship in Basic Biomedical Research [108501-53-RKNT]
- Canadian Institutes of Health Research operating grant [119334]
- Fonds de la recherche en sante du Quebec Chercheur Boursier Junior fellowship [24639]
- Canada Research Chair on Retroviral Entry
- NIH [AI24755, GM56550]
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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