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

  • Nat Chem Biol. 2014 Oct;10(10):845-52. doi: 10.1038/nchembio.1623.
Alon Herschhorn  1 ,  Christopher Gu  2 ,  Nicole Espy  1 ,  Jonathan Richard  3 ,  Andrés Finzi  4 ,  Joseph G Sodroski  5
Affiliations
  • 1. 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
  • 2. Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • 3. 1] Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montreal, Quebec, Canada. [2] Department of Microbiology, Infectiology and Immunology ,Université de Montréal, Montreal, Quebec, Canada.
  • 4. 1] Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, Montreal, Quebec, Canada. [2] Department of Microbiology, Infectiology and Immunology ,Université de Montréal, Montreal, Quebec, Canada. [3] Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
  • 5. 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA. [3] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
PMID: 25174000 DOI: 10.1038/nchembio.1623
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-110253
    18A
    HIV-1 Inhibitor
    target: HIV
    Research Areas: Infection