Abstract
BackgroundIntegrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs block the strand transfer reaction catalyzed by HIV-1 integrase (IN) and have been shown to potently inhibit infection by wild-type HIV-1. Of the three current FDA-approved INSTIs, Dolutegravir (DTG), has been the most effective, in part because treatment does not readily select for resistant mutants. However, recent studies showed that when INSTI-experienced patients are put on a DTG-salvage therapy, they have reduced response rates. Two new INSTIs, Cabotegravir (CAB) and Bictegravir (BIC), are currently in late-stage clinical trials.ResultsBoth CAB and BIC had much broader antiviral profiles than RAL and EVG against the INSTI-resistant single, double, and triple HIV-1 mutants used in this study. BIC was more effective than DTG against several INSTI-resistant mutants. Overall, in terms of their ability to inhibit a broad range of INSTI-resistant IN mutants, BIC was superior to DTG, and DTG was superior to CAB. Modeling the binding of CAB, BIC, and DTG within the active site of IN suggested that the “left side” of the INSTI pharmacophore (the side away from the viral DNA) was important in determining the ability of the compound to inhibit the IN mutants we tested.ConclusionsOf the two INSTIs in late stage clinical trials, BIC appears to be better able to inhibit the replication of a broad range of IN mutants. BIC retained potency against several of the INSTI-resistant mutants that caused a decrease in susceptibility to DTG.
Highlights
Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the Food and Drug Administration (FDA) for the treatment of human immunodeficiency virus (HIV)-1 infections
Initial screening of CAB and BIC against primary INSTI resistant mutants The abilities of CAB and BIC to inhibit the replication of WT HIV-1 and INSTI-resistant mutants were determined in single-round viral replication assays
The R263K mutation has been selected in several treatment-experienced, INSTInaïve patients undergoing DTG therapy [16]. Both CAB and BIC potently inhibited the infection of WT HIV-1 with half maximal inhibitory concentration (EC50) values equivalent to the FDA-approved INSTIs (< 3 nM)
Summary
Integrase strand transfer inhibitors (INSTIs) are the class of antiretroviral (ARV) drugs most recently approved by the FDA for the treatment of HIV-1 infections. INSTIs are the class of antiretroviral (ARV) drugs most recently approved by the FDA to treat HIV-1 infections. INSTIs have a centralized pharmacophore, which contains a chelating functionality that interacts with the two catalytic Mg2+ ions at the IN active site [3, 4]. This central pharmacophore is joined to a halogenated benzyl moiety that interacts with the penultimate base at the 3′ end of the viral DNA [5].
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