2. Academic Validation
  3. Structural basis of second-generation HIV integrase inhibitor action and viral resistance

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

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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