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
  • 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. [email protected].
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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-125183
    BMS-818251
    99.36%, HIV-1 Attachment and Entry Inhibitor
    target: HIV
    Research Areas: Infection