HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors
- University of Colorado School of Medicine, United States
- Emory University, United States
- Pace University, United States
- The Ohio State University, United States
- University of Colorado Denver, United States
- Dana-Farber Cancer Institute, United States
- Salk Institute for Biological Studies, United States
- 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
Article and author information
Author details
Daniel Adu-Ampratwum
Mamuka Kvaratskhelia
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
- Julie Overbaugh, Fred Hutchinson Cancer Research Center, United States
Version history
- Received: February 23, 2019
- Accepted: May 22, 2019
- Accepted Manuscript published: May 23, 2019 (version 1)
- Version of Record published: June 18, 2019 (version 2)
- Version of Record updated: June 21, 2019 (version 3)
- 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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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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