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A New Class Of Allosteric Hiv-1 Integrase Inhibitors Identified By Crstallographic Fragment Screening Of The Catalytic Core Domain, Disha Patel, Janet Antwi, Pratibha C. Koneru, Erik Serrao, Stefano Forli, Jacques J. Kessl, Lei Feng, Nanjie Deng, Ronald M. Levy, James R. Fuchs, Arthur J. Olson, Alan N. Engelman, Joseph D. Bauman, Mamuka Kvaratskhelia, Eddy Arnold
A New Class Of Allosteric Hiv-1 Integrase Inhibitors Identified By Crstallographic Fragment Screening Of The Catalytic Core Domain, Disha Patel, Janet Antwi, Pratibha C. Koneru, Erik Serrao, Stefano Forli, Jacques J. Kessl, Lei Feng, Nanjie Deng, Ronald M. Levy, James R. Fuchs, Arthur J. Olson, Alan N. Engelman, Joseph D. Bauman, Mamuka Kvaratskhelia, Eddy Arnold
Faculty Publications
HIV-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 …