Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants-Reference-Cited by-同舟云学术

Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants

Published:2023-07-21 Issue:29 Volume:9 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Li Min¹^ORCID,Oliveira Passos Dario²^ORCID,Shan Zelin²^ORCID,Smith Steven J.³^ORCID,Sun Qinfang⁴^ORCID,Biswas Avik²⁵^ORCID,Choudhuri Indrani⁴^ORCID,Strutzenberg Timothy S.²^ORCID,Haldane Allan⁵^ORCID,Deng Nanjie⁶^ORCID,Li Zhaoyang¹,Zhao Xue Zhi³^ORCID,Briganti Lorenzo⁷^ORCID,Kvaratskhelia Mamuka⁷^ORCID,Burke Terrence R.³^ORCID,Levy Ronald M.⁵^ORCID,Hughes Stephen H.³^ORCID,Craigie Robert¹^ORCID,Lyumkis Dmitry²⁸⁹^ORCID

Affiliation:

1. National Institute of Diabetes and Digestive Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.

2. The Salk Institute for Biological Studies, La Jolla, CA, 92037, USA.

3. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA.

4. Center for Biophysics and Computational Biology, and Department of Chemistry, Temple University, Philadelphia, PA 19122, USA.

5. Center for Biophysics and Computational Biology and Department of Physics, Temple University, Philadelphia, PA 19122, USA.

6. Department of Chemistry and Physical Sciences, Pace University, New York, NY, 10038, USA.

7. Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

8. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.

9. Graduate School of Biological Sciences, Section of Molecular Biology, University of California San Diego, La Jolla, CA 92093, USA.

Abstract

HIV-1 infection depends on the integration of viral DNA into host chromatin. Integration is mediated by the viral enzyme integrase and is blocked by integrase strand transfer inhibitors (INSTIs), first-line antiretroviral therapeutics widely used in the clinic. Resistance to even the best INSTIs is a problem, and the mechanisms of resistance are poorly understood. Here, we analyze combinations of the mutations E138K, G140A/S, and Q148H/K/R, which confer resistance to INSTIs. The investigational drug 4d more effectively inhibited the mutants compared with the approved drug Dolutegravir (DTG). We present 11 new cryo-EM structures of drug-resistant HIV-1 intasomes bound to DTG or 4d, with better than 3-Å resolution. These structures, complemented with free energy simulations, virology, and enzymology, explain the mechanisms of DTG resistance involving E138K + G140A/S + Q148H/K/R and show why 4d maintains potency better than DTG. These data establish a foundation for further development of INSTIs that potently inhibit resistant forms in integrase.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference88 articles.

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