1. Microbiology and Infectious Disease
  2. Structural Biology and Molecular Biophysics
Download icon

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
Research Article
  • Cited 24
  • Views 1,489
  • Annotations
Cite this article as: eLife 2018;7:e36340 doi: 10.7554/eLife.36340

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.

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.

Metrics

  • 1,489
    Page views
  • 280
    Downloads
  • 24
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Sytse J Piersma et al.
    Research Article Updated

    Recognition of DNA viruses, such as cytomegaloviruses (CMVs), through pattern-recognition receptor (PRR) pathways involving MyD88 or STING constitute a first-line defense against infections mainly through production of type I interferon (IFN-I). However, the role of these pathways in different tissues is incompletely understood, an issue particularly relevant to the CMVs which have broad tissue tropisms. Herein, we contrasted anti-viral effects of MyD88 versus STING in distinct cell types that are infected with murine CMV (MCMV). Bone marrow chimeras revealed STING-mediated MCMV control in hematological cells, similar to MyD88. However, unlike MyD88, STING also contributed to viral control in non-hematological, stromal cells. Infected splenic stromal cells produced IFN-I in a cGAS-STING-dependent and MyD88-independent manner, while we confirmed plasmacytoid dendritic cell IFN-I had inverse requirements. MCMV-induced natural killer cytotoxicity was dependent on MyD88 and STING. Thus, MyD88 and STING contribute to MCMV control in distinct cell types that initiate downstream immune responses.

    1. Biochemistry and Chemical Biology
    2. Microbiology and Infectious Disease
    Ali Alghamdi et al.
    Research Article

    Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.