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

Nature Chemical Biology volume 13, pages 1115–1122 (2017)Cite this article

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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.

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Figure 1: HIV-1-Env recognition by small-molecule entry inhibitor BMS-626529.
Figure 2: Detailed interactions of BMS-626529 with HIV-1 Env gp120.
Figure 3: Detailed interactions of BMS-378806 with HIV-1 Env gp120.
Figure 4: Induced-fit conformational changes.
Figure 5: Entry inhibition mechanism for BMS-378806 and BMS-626529 small molecules.

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Acknowledgements

We thank J. Stuckey for assistance with figures, members of Structural Biology and Structural Bioinformatics Core Sections, Vaccine Research Center for discussions and comments on the manuscript. We thank J. Baalwa (University of Alabama at Birmingham), D. Ellenberger (National Cancer Institute, NIH), F. Gao (Duke University), B. Hahn (University of Pennsylvania), K. Hong (Chinese Center for Disease Control and Prevention), J. Kim (The International Vaccine Institute), F. McCutchan (Military HIV Research Program), D. Montefiori (Duke University), L. Morris (National Institute of Communicable Diseases), J. Overbaugh (Fred Hutchison Cancer Research Center), E. Sanders-Buell (Military HIV Research Program), G. Shaw (University of Pennsylvania), R. Swanstrom (University of North Carolina at Chapel Hill), M. Thomson (Instituto de Salud Carlos III), S. Tovanabutra (Military HIV Research Program), C. Williamson (University of Cape Town) and L. Zhang (China Medical University Shenyang) for contributing the HIV-1 envelope plasmids used in our neutralization panel. We thank D. Burton (The Scripps Research Institute) and M. Feinberg (International AIDS Vaccine Initiative) for antibody PGT122 and M. Connors (National Institute of Allergy and Infectious Diseases, NIH) for antibody 35O22 used in structural analysis. 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 (J.S.), the National Science Foundation MCB-1157506 (E.F.) and the National Institutes of Health GM56550 (E.F.). 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.

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Authors and Affiliations

  1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Marie Pancera, Yen-Ting Lai, Tatsiana Bylund, Aliaksandr Druz, Sandeep Narpala, Sijy O'Dell, Robert T Bailer, Gwo-Yu Chuang, Hui Geng, Mark K Louder, Reda Rawi, Djade I Soumana, John R Mascola, Adrian B McDermott & Peter D Kwong

  2. Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA

    Arne Schön & Ernesto Freire

  3. Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada

    Andrés Finzi

  4. Department of Cancer Immunology and Virology, Dana–Farber Cancer Institute, Boston, Massachusetts, USA

    Alon Herschhorn, Navid Madani & Joseph Sodroski

  5. Computer Assisted Drug Design, Bristol-Myers Squibb, Research and Development, Wallingford, Connecticut, USA

    David R Langley

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Contributions

M.P. determined the structures with assistance from Y.-T.L., G.-Y.C., D.I.S., D.R.L. and P.D.K. T.B. and G.-Y.C. assisted in resistance analysis. S.N. and A.B.M. performed antigenic analyses. S.O'D., R.T.B., M.K.L. and J.R.M. performed neutralization experiments. A.S. and E.F. performed isothermal titration calorimetry experiments. A.D. expressed proteins, and H.G. and D.I.S. purified proteins. R.R. performed sequence entropy analysis. A.F., A.H., N.M. and J.S. contributed mutagenesis analyses and competition analysis with CD4. M.P. and P.D.K. analyzed the data and wrote the paper, with contributions from J.S. and D.R.L.

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Correspondence to Peter D Kwong.

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D.R.L. owns stock in Bristol-Myers Squibb.

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Pancera, M., Lai, YT., Bylund, T. et al. Crystal structures of trimeric HIV envelope with entry inhibitors BMS-378806 and BMS-626529. Nat Chem Biol 13, 1115–1122 (2017). https://doi.org/10.1038/nchembio.2460

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