February 28, 2020

Structural foundation of second-generation HIV integrase inhibitor motion and viral resistance

Strengths and weaknesses of an HIV drug

Retroviruses replicate by inserting a duplicate of their RNA, which has been reverse transcribed into DNA, into the host genome. This course of entails the intasome, a nucleoprotein advanced comprising copies of the viral integrase sure on the ends of the viral DNA. HIV integrase strand-transfer inhibitors (INSTIs) cease HIV from replicating by blocking the viral integrase and are extensively utilized in HIV therapy. Prepare dinner et al. describe buildings of second-generation inhibitors sure to the simian immunodeficiency virus (SIV) intasome and to an intasome with integrase mutations recognized to trigger drug resistance. Passos et al. describe the buildings of the HIV intasome sure to a second-generation inhibitor and to developmental compounds which are promising drug leads. These buildings present how mutations may cause delicate adjustments within the energetic web site that have an effect on drug binding, present the idea for the upper exercise of later-generation inhibitors, and will information growth of higher medicine.

Science, this situation p. 806, p. 810


Though second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed all through the world, the mechanistic foundation for the prevalence of those medicine is poorly understood. We used single-particle cryo–electron microscopy to visualise the mode of motion of the superior INSTIs dolutegravir and bictegravir at near-atomic decision. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that lead to medical INSTI failure perturb optimum magnesium ion coordination within the enzyme energetic web site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein spine which are important for antagonizing viruses containing the Q148H and G140S mutations. Our outcomes reveal that binding to magnesium ions underpins a basic weak point of the INSTI pharmacophore that’s exploited by the virus to engender resistance and supply a structural framework for the event of this class of anti-HIV/AIDS therapeutics.

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