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; Peter D. Kwong

doi:10.1038/s41467-018-07851-1

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, Peter D. Kwong

Medicine - Infectious Disease and International

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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.

Original language	English (US)
Article number	47
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07851-1
State	Published - Dec 1 2019

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Publisher Copyright:
© 2019, The Author(s).

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Lai, Y. T., Wang, T., O’Dell, S., Louder, M. K., Schön, A., Cheung, C. S. F., Chuang, G. Y., Druz, A., Lin, B., McKee, K., Peng, D., Yang, Y., Zhang, B., Herschhorn, A., Sodroski, J., Bailer, R. T., Doria-Rose, N. A., Mascola, J. R., Langley, D. R., & Kwong, P. D. (2019). Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry. Nature communications, 10(1), Article 47. https://doi.org/10.1038/s41467-018-07851-1

Lai, YT, Wang, T, O’Dell, S, Louder, MK, Schön, A, Cheung, CSF, Chuang, GY, Druz, A, Lin, B, McKee, K, Peng, D, Yang, Y, Zhang, B, Herschhorn, A, Sodroski, J, Bailer, RT, Doria-Rose, NA, Mascola, JR, Langley, DR & Kwong, PD 2019, 'Lattice engineering enables definition of molecular features allowing for potent small-molecule inhibition of HIV-1 entry', Nature communications, vol. 10, no. 1, 47. https://doi.org/10.1038/s41467-018-07851-1

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

Abstract

Bibliographical note

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