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Patel D , Antwi J , Koneru PC , Serrao E , Forli S , Kessl JJ , Feng L , Deng N , Levy RM , Fuchs JR , Olson AJ , Engelman AN , Bauman JD , Kvaratskhelia M , Arnold E
A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain
J Biol Chem. 2016 Nov 04;291(45) :23569-23577
PMID: 27645997    PMCID: PMC5095411   
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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 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 mum and impaired HIV-1 infection of T cells at an EC50 of 36 mum 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.
1083-351x Patel, Disha Antwi, Janet Koneru, Pratibha C Serrao, Erik Forli, Stefano Kessl, Jacques J Feng, Lei Deng, Nanjie Levy, Ronald M Fuchs, James R Olson, Arthur J Engelman, Alan N Bauman, Joseph D Kvaratskhelia, Mamuka Arnold, Eddy P50 GM103368/GM/NIGMS NIH HHS/United States R21 AI127282/AI/NIAID NIH HHS/United States R21 AI110270/AI/NIAID NIH HHS/United States R01 GM030580/GM/NIGMS NIH HHS/United States R01 AI110310/AI/NIAID NIH HHS/United States Journal Article United States J Biol Chem. 2016 Nov 4;291(45):23569-23577. Epub 2016 Sep 19.