Multimode, Cooperative Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors

Jacques J Kessl; Nivedita Jena; Yasuhiro Koh; Humeyra Taskent-Sezgin; Alison Slaughter; Lei Feng; Suresh de Silva; Li Wu; Stuart F. J Le Grice; Alan Engelman; James R Fuchs; Mamuka Kvaratskhelia

doi:10.1074/jbc.M112.354373

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Multimode, Cooperative Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors

Journal article

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Multimode, Cooperative Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors

Jacques J Kessl, Nivedita Jena, Yasuhiro Koh, Humeyra Taskent-Sezgin, Alison Slaughter, Lei Feng, Suresh de Silva, Li Wu, Stuart F. J Le Grice, Alan Engelman, …

The Journal of biological chemistry, Vol.287(20), pp.16801-16811

05/11/2012

DOI: 10.1074/jbc.M112.354373

PMCID: PMC3351293

PMID: 22437836

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Abstract

Background: 2-(Quinolin-3-yl)-acetic-acid derivatives target HIV-1 integrase and inhibit viral replication. Results: The compounds are allosteric integrase inhibitors (ALLINIs) that block integrase interactions with viral DNA and its cellular cofactor LEDGF and cooperatively inhibit HIV-1 replication. Conclusion: ALLINIs block multiple steps of HIV-1 integration. Significance: These new properties of ALLINIs will facilitate their further development as potent antiretroviral compounds. The multifunctional HIV-1 enzyme integrase interacts with viral DNA and its key cellular cofactor LEDGF to effectively integrate the reverse transcript into a host cell chromosome. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Recently, 2-(quinolin-3-yl) acetic acid derivatives were reported to selectively inhibit the integrase-LEDGF interaction in vitro and impair HIV-1 replication in infected cells. Here, we show that this class of compounds impairs both integrase-LEDGF binding and LEDGF-independent integrase catalytic activities with similar IC 50 values, defining them as bona fide allosteric inhibitors of integrase function. Furthermore, we show that 2-(quinolin-3-yl) acetic acid derivatives block the formation of the stable synaptic complex between integrase and viral DNA by allosterically stabilizing an inactive multimeric form of integrase. In addition, these compounds inhibit LEDGF binding to the stable synaptic complex. This multimode mechanism of action concordantly results in cooperative inhibition of the concerted integration of viral DNA ends in vitro and HIV-1 replication in cell culture. Our findings, coupled with the fact that high cooperativity of antiviral inhibitors correlates with their increased instantaneous inhibitory potential, an important clinical parameter, argue strongly that improved 2-(quinolin-3-yl) acetic acid derivatives could exhibit desirable clinical properties.

HIV-1

Integrase

Molecular Bases of Disease

Protein-DNA Interaction

Allosteric Regulation

Protein-Protein Interactions

Details

Title: Subtitle: Multimode, Cooperative Mechanism of Action of Allosteric HIV-1 Integrase Inhibitors
Creators: Jacques J Kessl - Center for Retrovirus Research and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210
Nivedita Jena - Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210
Yasuhiro Koh - Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215
Humeyra Taskent-Sezgin - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
Alison Slaughter - Center for Retrovirus Research and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210
Lei Feng - Center for Retrovirus Research and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210
Suresh de Silva - HIV Drug Resistance Program, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201, and
Li Wu - HIV Drug Resistance Program, National Cancer Institute at Frederick, Frederick, Maryland 21702-1201, and
Stuart F. J Le Grice - Center for Retrovirus Research, Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210
Alan Engelman - Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215
James R Fuchs - Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210
Mamuka Kvaratskhelia - Center for Retrovirus Research and Comprehensive Cancer Center, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.287(20), pp.16801-16811
DOI: 10.1074/jbc.M112.354373
PMID: 22437836
PMCID: PMC3351293
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology; 9650 Rockville Pike, Bethesda, MD 20814, U.S.A
Grant note: AI081581; AI062520; CA100730; AI039394 / National Institutes of Health
Alternative title: Allosteric HIV-1 Integrase Inhibitors
Language: English
Date published: 05/11/2012
Academic Unit: Microbiology and Immunology
Record Identifier: 9984001119302771

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