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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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 languageEnglish (US)
Article number47
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
We thank D. Burton and M. Fineberg for the sequences of NAC-identified antibodies, including the 3H109L member of the PGT121 lineage used in crystallization, M. Connors for the sequence of antibody 35O22 used in crystallization, J. Stuckey for assistance with figures, and members of Structural Biology and Structural Bioinformatics Core Sections, Vaccine Research Center for discussions and comments on the manuscript and the WCMC/AMC/TSRI HIVRAD team for their contributions to the design and validation of near-native mimicry for soluble BG505 SOSIP.664 trimers. Funding was provided by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, the Intramural AIDS Targeted Antiretroviral Program, the National Institute of General Medical Sciences, National Institutes of Health. Use of sector 22 (Southeast Region Collaborative Access team) at the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under contract no. W-31-109-Eng-38.

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

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