title: A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain.
abstract: 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 IC50of 72 μm and impaired HIV-1 infection of T cells at an EC50of 36 μm 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.
authors.affiliation: From the Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Disha
authors.initials: D
authors.lastname: Patel
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and.
authors.forename: Janet
authors.initials: J
authors.lastname: Antwi
authors.affiliation: Center for Retrovirus Research and College of Pharmacy, Ohio State University, Columbus, Ohio 43210.
authors.forename: Pratibha C
authors.initials: PC
authors.lastname: Koneru
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Erik
authors.initials: E
authors.lastname: Serrao
authors.affiliation: Molecular Graphics Laboratory, Department of Integrative Structural and Computational Biology, MB-112, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Stefano
authors.initials: S
authors.lastname: Forli
authors.affiliation: Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, Mississippi 39406, and.
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Kessl
authors.affiliation: Center for Retrovirus Research and College of Pharmacy, Ohio State University, Columbus, Ohio 43210.
authors.forename: Lei
authors.initials: L
authors.lastname: Feng
authors.affiliation: Center for Biophysics and Computational Biology, Temple University, Philadelphia, Pennsylvania 19122.
authors.forename: Nanjie
authors.initials: N
authors.lastname: Deng
authors.affiliation: Center for Biophysics and Computational Biology, Temple University, Philadelphia, Pennsylvania 19122.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Levy
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and.
authors.forename: James R
authors.initials: JR
authors.lastname: Fuchs
authors.affiliation: Molecular Graphics Laboratory, Department of Integrative Structural and Computational Biology, MB-112, The Scripps Research Institute, La Jolla, California 92037.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Engelman
authors.affiliation: From the Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bauman
authors.affiliation: Center for Retrovirus Research and College of Pharmacy, Ohio State University, Columbus, Ohio 43210, kvaratskhelia.1@osu.edu.
authors.forename: Mamuka
authors.initials: M
authors.lastname: Kvaratskhelia
authors.affiliation: From the Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, arnold@cabm.rutgers.edu.
authors.forename: Eddy
authors.initials: E
authors.lastname: Arnold
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002264:Carboxylic Acids; D019428:HIV Integrase Inhibitors; D013876:Thiophenes; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1
keywords: HIV-1; HIV-1 integrase; X-ray crystallography; allosteric inhibitor; drug discovery; drug screening; fragment screening; human immunodeficiency virus (HIV); integrase; medicinal chemistry