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

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, Alon Herschhorn, Joseph Sodroski, Robert T. Bailer, Nicole A. Doria-Rose, John R. Mascola, David R. Langley and Peter D. Kwong ()
Additional contact information
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
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

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07851-1

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