5krs

Publication Abstract from PubMed

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 LEDGF/p75 binding pocket. The most active fragment 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. These findings are significant because the identified lead fragment with a relatively small molecular weight (221 Da) provides an optimal building block for developing a new class of inhibitors. Furthermore, while structurally distinct thiophenecarboxylic acid-derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead fragment 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.

A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain.,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 J Biol Chem. 2016 Sep 19. pii: jbc.M116.753384. PMID:27645997^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.