HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors

  1. Pratibha C Koneru
  2. Ashwanth C Francis
  3. Nanjie Deng
  4. Stephanie V Rebensburg
  5. Ashley C Hoyte
  6. Jared Lindenberger
  7. Daniel Adu-Ampratwum
  8. Ross C Larue
  9. Michael F Wempe
  10. Alan N Engelman
  11. Dmitry Lyumkis
  12. James R Fuchs
  13. Ronald M Levy
  14. Gregory B Melikyan
  15. Mamuka Kvaratskhelia  Is a corresponding author
  1. University of Colorado School of Medicine, United States
  2. Emory University, United States
  3. Pace University, United States
  4. The Ohio State University, United States
  5. University of Colorado Denver, United States
  6. Dana-Farber Cancer Institute, United States
  7. Salk Institute for Biological Studies, United States
  8. Temple University, United States

Abstract

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising new class of antiretroviral agents that disrupt proper viral maturation by inducing hyper-multimerization of IN. Here we show that lead pyridine-based ALLINI KF116 exhibits striking selectivity for IN tetramers versus lower order protein oligomers. IN structural features that are essential for its functional tetramerization and HIV-1 replication are also critically important for KF116 mediated higher-order IN multimerization. Live cell imaging of single viral particles revealed that KF116 treatment during virion production compromises the tight association of IN with capsid cores during subsequent infection of target cells. We have synthesized the highly active (-)-KF116 enantiomer, which displayed EC50 of ~7 nM against wild type HIV-1 and ~10-fold higher, sub-nM activity against a clinically relevant dolutegravir resistant mutant virus suggesting potential clinical benefits for complementing dolutegravir therapy with pyridine-based ALLINIs.

Data availability

Diffraction data have been deposited in PDB under the accession code 6NUJ

The following data sets were generated

Article and author information

Author details

  1. Pratibha C Koneru

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ashwanth C Francis

    Department of Pediatrics, Infectious Diseases, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nanjie Deng

    Department of Chemistry and Physical Sciences, Pace University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Stephanie V Rebensburg

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ashley C Hoyte

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jared Lindenberger

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Daniel Adu-Ampratwum

    College of Pharmacy, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9392-2431
  8. Ross C Larue

    College of Pharmacy, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michael F Wempe

    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Alan N Engelman

    Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Dmitry Lyumkis

    Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8124-7472
  12. James R Fuchs

    College of Pharmacy, The Ohio State University, Columbus, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Ronald M Levy

    Department of Chemistry, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8696-5177
  14. Gregory B Melikyan

    Department of Pediatrics, Infectious Diseases, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Mamuka Kvaratskhelia

    Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, United States
    For correspondence
    MAMUKA.KVARATSKHELIA@UCDENVER.EDU
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3800-0033

Funding

National Institutes of Health (U54GM103368)

  • Mamuka Kvaratskhelia

National Institutes of Health (R01AI062520)

  • Mamuka Kvaratskhelia

National Institutes of Health (KL2 TR001068)

  • Ross C Larue

National Institutes of Health (R37AI039394)

  • Alan N Engelman

National Institutes of Health (R01AI143649)

  • Mamuka Kvaratskhelia

National Institutes of Health (R01AI129862)

  • Gregory B Melikyan

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

Reviewing Editor

  1. Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States

Publication history

  1. Received: February 23, 2019
  2. Accepted: May 22, 2019
  3. Accepted Manuscript published: May 23, 2019 (version 1)
  4. Version of Record published: June 18, 2019 (version 2)
  5. Version of Record updated: June 21, 2019 (version 3)
  6. Version of Record updated: July 15, 2020 (version 4)

Copyright

© 2019, Koneru 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. Pratibha C Koneru
  2. Ashwanth C Francis
  3. Nanjie Deng
  4. Stephanie V Rebensburg
  5. Ashley C Hoyte
  6. Jared Lindenberger
  7. Daniel Adu-Ampratwum
  8. Ross C Larue
  9. Michael F Wempe
  10. Alan N Engelman
  11. Dmitry Lyumkis
  12. James R Fuchs
  13. Ronald M Levy
  14. Gregory B Melikyan
  15. Mamuka Kvaratskhelia
(2019)
HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors
eLife 8:e46344.
https://doi.org/10.7554/eLife.46344

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