Structure-Based Hit Identification of Allosteric HIV Integrase Inhibitors
HIV Integrase catalyzes the incorporation of viral DNA into the host genome and is a critical part of the viral life cycle. As a result, integrase has been a protein of therapeutic interest for several decades and, to date, three integrase inhibitors have been approved for clinical use (raltegravir, dolutegravir, and elvitegravir). Clinically significant resistance mutations to drugs targeting HIV integrase have emerged with integrase inhibitor-containing treatment regimens and efforts to develop novel inhibitors of HIV integrase that overcome viral resistance have resulted in the identification of compounds with allosteric binding sites and non-canonical mechanisms of inhibition. An example of these efforts is the broad class of compounds which bind in the LEDGF/p75 binding site on HIV integrase and disrupt the association of these two proteins. Integrase inhibitors displaying this mechanism of action have been shown to possess significant antiviral potency, motivating additional discovery efforts in this area. We describe virtual screening, crystallographic, and additional computational efforts directed towards the identification of novel, allosteric integrase inhibitors.