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HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes

Nature Chemical Biology volume 16, pages 529–537 (2020)Cite this article

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Abstract

Combination antiretroviral therapy has transformed HIV-1 infection, once a fatal illness, into a manageable chronic condition. Drug resistance, severe side effects and treatment noncompliance bring challenges to combination antiretroviral therapy implementation in clinical settings and indicate the need for additional molecular targets. Here, we have identified several small-molecule fusion inhibitors, guided by a neutralizing antibody, against an extensively studied vaccine target—the membrane proximal external region (MPER) of the HIV-1 envelope spike. These compounds specifically inhibit the HIV-1 envelope-mediated membrane fusion by blocking CD4-induced conformational changes. An NMR structure of one compound complexed with a trimeric MPER construct reveals that the compound partially inserts into a hydrophobic pocket formed exclusively by the MPER residues, thereby stabilizing its prefusion conformation. These results suggest that the MPER is a potential therapeutic target for developing fusion inhibitors and that strategies employing an antibody-guided search for novel therapeutics may be applied to other human diseases.

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Fig. 1: Identification of dequalinium as a small-molecule fusion inhibitor targeting the MPER of HIV-1 Env.
Fig. 2: SAR study using synthesized dequalinium analogs.
Fig. 3: Characterization of the most potent compound S2C3.
Fig. 4: Structure of S2C3 in complex with the MPER-TMD.

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Data availability

The atomic structure coordinates and NMR data are deposited in the Protein Data Bank under the accession number 6V4T. All other related data generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank H.J. Ha, D. O’Neil Danis III, S. Rits-Volloch, H. Peng, Z. Liu, and the staff at ICCB-Longwood for technical assistance. This work was supported by NIH grant nos AI129721 (to B.C.), AI112489 (to B.C.), AI127193 (to B.C. and J.J.C.), GM116898 (to J.J.C.), AI141002 (to B.C.) and AI106488 (to B.C.). The NMR data were collected on a 800 MHz NMR spectrometer at MIT-Harvard CMR (supported by NIH grant no. P41 EB-002026) and on a 900 MHz NMR spectrometer at the National Facility for Protein Science in Shanghai, ZhangJiang Laboratory.

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Author notes

  1. Gary Frey

    Present address: ICCB-Longwood Screening Facility, Harvard Medical School, Boston, MA, USA

  2. These authors contributed equally: Tianshu Xiao, Gary Frey.

Authors and Affiliations

  1. Division of Molecular Medicine, Boston Children’s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA

    Tianshu Xiao, Gary Frey & Bing Chen

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Qingshan Fu & James J. Chou

  3. Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Christy L. Lavine & Michael S. Seaman

  4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    David A. Scott

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Contributions

B.C., G.F. and T.X. conceived the project. G.F. developed the fluorescence polarization assay and performed the HTS. T.X. and G.F. performed biochemical and functional studies on the hit compounds. G.F. and D.A.S. designed dequalinium analogs. T.X., Q.F. and J.J.C. carried out the NMR studies. C.L.L. and M.S.S. performed the pseudovirus assays. All authors analyzed the data. B.C., T.X., J.J.C. and G.F. wrote the manuscript with input from all other authors.

Corresponding author

Correspondence to Bing Chen.

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Competing Interests

Boston Children’s Hospital has filed a patent application based on this work with B.C., G.F. and T.X. listed as co-inventors. All other authors declare no competing interests.

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Xiao, T., Frey, G., Fu, Q. et al. HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes. Nat Chem Biol 16, 529–537 (2020). https://doi.org/10.1038/s41589-020-0496-y

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