2. Academic Validation
  3. Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry

Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry

  • Nat Commun. 2019 Jan 3;10(1):47. doi: 10.1038/s41467-018-07851-1.
Yen-Ting Lai 1,  Tao Wang 2,  Sijy O'Dell 1,  Mark K Louder 1,  Arne Schön 3,  Crystal S F Cheung 1,  Gwo-Yu Chuang 1,  Aliaksandr Druz 1,  Bob Lin 1,  Krisha McKee 1,  Dongjun Peng 1,  Yongping Yang 1,  Baoshan Zhang 1,  Alon Herschhorn 4 5,  Joseph Sodroski 4,  Robert T Bailer 1,  Nicole A Doria-Rose 1,  John R Mascola 1,  David R Langley 6,  Peter D Kwong 7
Affiliations

Affiliations

  • 1 Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, 20892, USA.
  • 2 Departments of Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, Cambridge, MA, 02142, USA.
  • 3 Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA.
  • 4 Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
  • 5 Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 6 Computer Assisted Drug Design, Bristol-Myers Squibb Research and Development, Wallingford, CT, 06492, USA.
  • 7 Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, 20892, USA. pdkwong@nih.gov.
PMID: 30604750 DOI: 10.1038/s41467-018-07851-1
Abstract

Diverse entry inhibitors targeting the gp120 subunit of the HIV-1 envelope (Env) trimer have been developed including BMS-626529, also called temsavir, a prodrug version of which is currently in phase III clinical trials. Here we report the characterization of a panel of small-molecule inhibitors including BMS-818251, which we show to be >10-fold more potent than temsavir on a cross-clade panel of 208-HIV-1 strains, as well as the engineering of a crystal lattice to enable structure determination of the interaction between these inhibitors and the HIV-1 Env trimer at higher resolution. By altering crystallization lattice chaperones, we identify a lattice with both improved diffraction and robust co-crystallization of HIV-1 Env trimers from different clades complexed to entry inhibitors with a range of binding affinities. The improved diffraction reveals BMS-818251 to utilize functional groups that interact with gp120 residues from the conserved β20-β21 hairpin to improve potency.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125183
    HIV-1 Entry Inhibitor
    HIV