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J Biol Chem. 2016 Nov 4;291(45):23569-23577. Epub 2016 Sep 19.

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

Author information

1
From the Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854.
2
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy and.
3
Center for Retrovirus Research and College of Pharmacy, Ohio State University, Columbus, Ohio 43210.
4
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215.
5
Molecular Graphics Laboratory, Department of Integrative Structural and Computational Biology, MB-112, The Scripps Research Institute, La Jolla, California 92037.
6
Department of Chemistry and Biochemistry, University of Southern Mississippi, Hattiesburg, Mississippi 39406, and.
7
Center for Biophysics and Computational Biology, Temple University, Philadelphia, Pennsylvania 19122.
8
Center for Retrovirus Research and College of Pharmacy, Ohio State University, Columbus, Ohio 43210, kvaratskhelia.1@osu.edu.
9
From the Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey 08854, arnold@cabm.rutgers.edu.

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 IC50 of 72 μm and impaired HIV-1 infection of T cells at an EC50 of 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.

KEYWORDS:

HIV-1; HIV-1 integrase; X-ray crystallography; allosteric inhibitor; drug discovery; drug screening; fragment screening; human immunodeficiency virus (HIV); integrase; medicinal chemistry

PMID:
27645997
PMCID:
PMC5095411
DOI:
10.1074/jbc.M116.753384
[Indexed for MEDLINE]
Free PMC Article

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