Structural basis of second-generation HIV integrase inhibitor action and viral resistance

  • Science. 2020 Feb 14;367(6479):806-810. doi: 10.1126/science.aay4919.
Nicola J Cook  1 ,  Wen Li  2  3 ,  Dénes Berta  4 ,  Magd Badaoui  4 ,  Allison Ballandras-Colas  1 ,  Andrea Nans  5 ,  Abhay Kotecha  6  7 ,  Edina Rosta  4 ,  Alan N Engelman  8  3 ,  Peter Cherepanov  9  10
Affiliations
  • 1. Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute, London NW1 1AT, UK.
  • 2. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 4. Department of Chemistry, King's College London, London SE1 1DB, UK.
  • 5. Structural Biology Science Technology Platform, Francis Crick Institute, London NW1 1AT, UK.
  • 6. The Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 7. Materials and Structural Analysis, Thermo Fisher Scientific, Eindhoven, 5651 GG, Netherlands.
  • 8. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. [email protected] [email protected].
  • 9. Chromatin Structure and Mobile DNA Laboratory, Francis Crick Institute, London NW1 1AT, UK. [email protected] [email protected].
  • 10. Department of Infectious Disease, Imperial College London, St Mary's Campus, London W2 1PG, UK.
PMID: 32001525 DOI: 10.1126/science.aay4919
Abstract

Although second-generation HIV Integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.

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