A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase

• DOI: 10.1371/journal.ppat.1004171
• Publication Date: 2014-05-29T20:38:11Z
• Authors: Amit Sharma; Alison Slaughter; Nivedita Jena; Lei Feng; Jacques J. Kessl; Hind J. Fadel; Nirav Malani; Frances Male; Li Wu; Eric Poeschla; Frederic D. Bushman; James R. Fuchs; Mamuka Kvaratskhelia
• Keywords: Quinoline; Integrase inhibitor

The quinoline-based allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are promising candidates for clinically useful antiviral agents. Studies using these compounds have highlighted the role of IN in both early and late stages virus replication. However, dissecting exact mechanism action ALLINIs has been complicated by multifunctional nature because they inhibit binding with its cofactor LEDGF/p75 promote aberrant multimerization similar potencies vitro. Here we report design small molecules that allowed us to probe independently from IN-LEDGF/p75 interactions infected cells. We altered rigid quinoline moiety designed pyridine-based a rotatable single bond allow bridge between interacting subunits optimally oligomerization. most potent inhibitor, KF116, potently (EC50 0.024 µM) blocked replication inducing particles, whereas it was not effective when added target Furthermore, KF116 inhibited variant A128T substitution, which confers resistance majority ALLINIs. A genome-wide integration site analysis demonstrated addition or producer cells did affect LEDGF/p75-dependent host chromosomes, indicating this compound is detectably inhibiting binding. These findings delineate significance correctly ordered structure particle morphogenesis demonstrate feasibility exploiting as therapeutic target. present novel class selective investigational probes molecular biology.