Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529

Marie Pancera, Yen Ting Lai, Tatsiana Bylund, Aliaksandr Druz, Sandeep Narpala, Sijy O'Dell, Arne Schön, Robert T. Bailer, Gwo Yu Chuang, Hui Geng, Mark K. Louder, Reda Rawi, Djade I. Soumana, Andrés Finzi, Alon Herschhorn, Navid Madani, Joseph Sodroski, Ernesto Freire, David R. Langley, John R. MascolaAdrian B. McDermott, Peter D. Kwong

Research output: Contribution to journalArticlepeer-review

Abstract

The HIV-1 envelope (Env) spike is a conformational machine that transitions between prefusion (closed, CD4- and CCR5-bound) and postfusion states to facilitate HIV-1 entry into cells. Although the prefusion closed conformation is a potential target for inhibition, development of small-molecule leads has been stymied by difficulties in obtaining structural information. Here, we report crystal structures at 3.8-Å resolution of an HIV-1-Env trimer with BMS-378806 and a derivative BMS-626529 for which a prodrug version is currently in Phase III clinical trials. Both lead candidates recognized an induced binding pocket that was mostly excluded from solvent and comprised of Env elements from a conserved helix and the β20-21 hairpin. In both structures, the β20-21 region assumed a conformation distinct from prefusion-closed and CD4-bound states. Together with biophysical and antigenicity characterizations, the structures illuminate the allosteric and competitive mechanisms by which these small-molecule leads inhibit CD4-induced structural changes in Env.

Original languageEnglish (US)
Pages (from-to)1115-1122
Number of pages8
JournalNature chemical biology
Volume13
Issue number10
DOIs
StatePublished - Oct 1 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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