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

Author

Listed:
  • Yen-Ting Lai

    (National Institutes of Health)

  • Tao Wang

    (Bristol-Myers Squibb Research and Development)

  • Sijy O’Dell

    (National Institutes of Health)

  • Mark K. Louder

    (National Institutes of Health)

  • Arne Schön

    (Johns Hopkins University)

  • Crystal S. F. Cheung

    (National Institutes of Health)

  • Gwo-Yu Chuang

    (National Institutes of Health)

  • Aliaksandr Druz

    (National Institutes of Health)

  • Bob Lin

    (National Institutes of Health)

  • Krisha McKee

    (National Institutes of Health)

  • Dongjun Peng

    (National Institutes of Health)

  • Yongping Yang

    (National Institutes of Health)

  • Baoshan Zhang

    (National Institutes of Health)

  • Alon Herschhorn

    (Harvard Medical School
    University of Minnesota)

  • Joseph Sodroski

    (Harvard Medical School)

  • Robert T. Bailer

    (National Institutes of Health)

  • Nicole A. Doria-Rose

    (National Institutes of Health)

  • John R. Mascola

    (National Institutes of Health)

  • David R. Langley

    (Bristol-Myers Squibb Research and Development)

  • Peter D. Kwong

    (National Institutes of Health)

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.

Suggested Citation

  • Yen-Ting Lai & Tao Wang & Sijy O’Dell & Mark K. Louder & Arne Schön & Crystal S. F. Cheung & Gwo-Yu Chuang & Aliaksandr Druz & Bob Lin & Krisha McKee & Dongjun Peng & Yongping Yang & Baoshan Zhang & A, 2019. "Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07851-1
    DOI: 10.1038/s41467-018-07851-1
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    Cited by:

    1. Jérémie Prévost & Yaozong Chen & Fei Zhou & William D. Tolbert & Romain Gasser & Halima Medjahed & Manon Nayrac & Dung N. Nguyen & Suneetha Gottumukkala & Ann J. Hessell & Venigalla B. Rao & Edwin Poz, 2023. "Structure-function analyses reveal key molecular determinants of HIV-1 CRF01_AE resistance to the entry inhibitor temsavir," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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