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

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 in...

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Published in:Nature communications 2019-01, Vol.10 (1), p.47-11, Article 47
Main Authors: Lai, Yen-Ting, Wang, Tao, O’Dell, Sijy, Louder, Mark K., Schön, Arne, Cheung, Crystal S. F., Chuang, Gwo-Yu, Druz, Aliaksandr, Lin, Bob, McKee, Krisha, Peng, Dongjun, Yang, Yongping, Zhang, Baoshan, Herschhorn, Alon, Sodroski, Joseph, Bailer, Robert T., Doria-Rose, Nicole A., Mascola, John R., Langley, David R., Kwong, Peter D.
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Language:English
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Summary: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. Temsavir, a compound that inhibits HIV entry by binding envelope (Env), is currently in clinical development. Here, Lai et al. identify a more than 10-fold improved compound and, using lattice engineering, obtain crystal structures that give insights into improved inhibition between small molecules and Env.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-07851-1