Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors

  1. Yang Yang
  2. Dongwei Kang
  3. Laura A Nguyen
  4. Zachary B Smithline
  5. Christophe Pannecouque
  6. Peng Zhan  Is a corresponding author
  7. Xinyong Liu  Is a corresponding author
  8. Thomas A Steitz  Is a corresponding author
  1. Yale University, United States
  2. Shandong University, China
  3. KU Leuven, Belgium

Abstract

Rapid generation of drug-resistant mutations in HIV-1 reverse transcriptase (RT), a prime target for anti-HIV therapy, poses a major impediment to effective anti-HIV treatment. Our previous efforts have led to the development of two novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds, compounds K-5a2 and 25a, which demonstrate highly potent anti-HIV-1 activities and improved resistance profiles compared with etravirine and rilpivirine, respectively. Here, we have determined the crystal structures of HIV-1 wild-type (WT) RT and seven RT variants bearing prevalent drug-resistant mutations in complex with K-5a2 or 25a at ~2 Å resolution. These high-resolution structures illustrate the molecular details of the extensive hydrophobic interactions and the network of main chain hydrogen bonds formed between the NNRTIs and the RT inhibitor binding pocket, and provide valuable insights into the favorable structural features that can be employed for designing NNRTIs that are broadly active against drug-resistant HIV-1 variants.

Data availability

Diffraction data and atomic coordinates have been deposited in the Protein Data Bank under the accession codes 6C0J, 6C0K, 6C0L, 6CGF, 6C0N, 6C0O, 6C0P, 6C0R, 6DUF, 6DUG, and 6DUH.

The following data sets were generated
The following previously published data sets were used
    1. Lansdon EB
    (2010) HIV-1 Reverse Transcriptase in Complex with TMC125
    Publicly available at the RCSB Protein Data Bank (accession no. 3MEC).

Article and author information

Author details

  1. Yang Yang

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9061-3828
  2. Dongwei Kang

    Department of Medicinal Chemistry, Shandong University, Jinan, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9232-953X
  3. Laura A Nguyen

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Zachary B Smithline

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christophe Pannecouque

    Rega Institute for Medical Research, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Peng Zhan

    Department of Medicinal Chemistry, Shandong University, Jinan, China
    For correspondence
    zhanpeng1982@sdu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  7. Xinyong Liu

    Department of Medicinal Chemistry, Shandong University, Jinan, China
    For correspondence
    xinyongl@sdu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  8. Thomas A Steitz

    Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, United States
    For correspondence
    thomas.steitz@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3357-3505

Funding

Howard Hughes Medical Institute (Investigator Program)

  • Thomas A Steitz

National Institute of General Medical Sciences (GM022778)

  • Thomas A Steitz

National Natural Science Foundation of China (81273354)

  • Xinyong Liu

Key research and development project of Shandong Province (2017CXGC1401)

  • Xinyong Liu

Major Project of Science and Technology of Shandong Province (2015ZDJS04001)

  • Xinyong Liu

Young Scholars Program of Shandong University (2016WLJH32)

  • Peng Zhan

Key Project of National Natural Science Foundation of China for International Cooperation (81420108027)

  • Xinyong Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Axel T Brunger, Stanford University, United States

Publication history

  1. Received: March 2, 2018
  2. Accepted: July 18, 2018
  3. Accepted Manuscript published: July 25, 2018 (version 1)
  4. Version of Record published: August 7, 2018 (version 2)

Copyright

© 2018, Yang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yang Yang
  2. Dongwei Kang
  3. Laura A Nguyen
  4. Zachary B Smithline
  5. Christophe Pannecouque
  6. Peng Zhan
  7. Xinyong Liu
  8. Thomas A Steitz
(2018)
Structural basis for potent and broad inhibition of HIV-1 RT by thiophene[3,2-d]pyrimidine non-nucleoside inhibitors
eLife 7:e36340.
https://doi.org/10.7554/eLife.36340

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