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

Authors

Disha Patel, Rutgers University
Janet Antwi, Ohio State UniversityFollow
Pratibha C. Koneru, Ohio State University
Erik Serrao, Harvard Medical School
Stefano Forli, The Scripps Research Institute
Jacques J. Kessl, University of Southern MississippiFollow
Lei Feng, Ohio State University
Nanjie Deng, Temple University
Ronald M. Levy, Temple University
James R. Fuchs, Ohio State UniversityFollow
Arthur J. Olson, The Scripps Research Institute
Alan N. Engelman, Harvard Medical School
Joseph D. Bauman, Rutgers University
Mamuka Kvaratskhelia, Ohio State UniversityFollow
Eddy Arnold, Rutgers UniversityFollow

Document Type

Article

Publication Date

9-19-2016

Department

Chemistry and Biochemistry

School

Mathematics and Natural Sciences

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.

Comments

Publisher's Version

Publication Title

Journal of Biological Chemistry

Volume

291

Issue

45

First Page

23569

Last Page

23577

Recommended Citation

Patel, D., Antwi, J., Koneru, P. C., Serrao, E., Forli, S., Kessl, J. J., Feng, L., Deng, N., Levy, R. M., Fuchs, J. R., Olson, A. J., Engelman, A. N., Bauman, J. D., Kvaratskhelia, M., Arnold, E. (2016). A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crstallographic Fragment Screening of the Catalytic Core Domain. Journal of Biological Chemistry, 291(45), 23569-23577.
Available at: https://aquila.usm.edu/fac_pubs/16743