A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain

Patel, DishaAntwi, JanetKoneru, PratibhaSerrao, ErikForli, StefanoKessl, JacquesFeng, LeiDeng, NanjieLevy, RonaldFuchs, JamesOlson, ArthurEngelman, AlanBauman, JosephKvaratskhelia, MamukaArnold, Eddy2019-10-052016Patel, Disha, Janet Antwi, Pratibha C. Koneru, Erik Serrao, Stefano Forli, Jacques J. Kessl, Lei Feng, et al. 2016. “A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain.” Journal of Biological Chemistry 291 (45): 23569–77. https://doi.org/10.1074/jbc.m116.753384.0021-92581083-351Xhttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41482919HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC50 of 72 m and impaired HIV-1 infection of T cells at an EC50 of 36 m. The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structure-based development of second-generation ALLINIs.en-USA New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core DomainJournal Article2019-10-0510.1074/jbc.M116.753384