Structural basis of second-generation HIV integrase inhibitor action and viral resistance
journal contributionposted on 07.09.2020, 11:04 by Nicola J Cook, Wen Li, Dénes Berta, Magd Badaoui, Allison Ballandras-Colas, Andrea Nans, Abhay Kotecha, Edina Rosta, Alan N Engelman, Peter Cherepanov
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.
Crick (Grant ID: 10061, Grant title: Cherepanov FC001061)
Amino Acid SubstitutionCatalytic DomainCryoelectron MicroscopyDrug Resistance, ViralGlutamineGlycineHIV IntegraseHIV Integrase InhibitorsHeterocyclic Compounds, 3-RingHeterocyclic Compounds, 4 or More RingsHistidineHumansMagnesiumMutationSerineSingle Molecule ImagingSBCherepanov FC001061EM-ackSC-ackGeneral Science & Technology