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Inhibition of human immunodeficiency virus type-1 by cdk inhibitors

Irene Guendel13, Emmanuel T Agbottah2, Kylene Kehn-Hall3 and Fatah Kashanchi134*

  • * Corresponding author: Fatah Kashanchi bcmfxk@gwumc.edu

  • † Equal contributors

Author Affiliations

1 Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, DC, 20037, USA

2 Department of Biochemistry and Molecular Biology, The George Washington University School of Medicine, Washington, DC, 20037, USA

3 Department of Molecular and Microbiology, National Center for Biodefense & Infectious Diseases, George Mason University, Manassas, VA 20110, USA

4 Keck Institute for Proteomics Technology and Applications, The George Washington University, Washington, DC, 20037, USA

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AIDS Research and Therapy 2010, 7:7  doi:10.1186/1742-6405-7-7

Published: 24 March 2010

Abstract

Current therapy for human immunodeficiency virus (HIV-1) infection relies primarily on the administration of anti-retroviral nucleoside analogues, either alone or in combination with HIV-protease inhibitors. Although these drugs have a clinical benefit, continuous therapy with the drugs leads to drug-resistant strains of the virus. Recently, significant progress has been made towards the development of natural and synthetic agents that can directly inhibit HIV-1 replication or its essential enzymes. We previously reported on the pharmacological cyclin-dependent kinase inhibitor (PCI) r-roscovitine as a potential inhibitor of HIV-1 replication. PCIs are among the most promising novel antiviral agents to emerge over the past few years. Potent activity on viral replication combined with proliferation inhibition without the emergence of resistant viruses, which are normally observed in HAART patients; make PCIs ideal candidates for HIV-1 inhibition. To this end we evaluated twenty four cdk inhibitors for their effect on HIV-1 replication in vitro. Screening of these compounds identified alsterpaullone as the most potent inhibitor of HIV-1 with activity at 150 nM. We found that alsterpaullone effectively inhibits cdk2 activity in HIV-1 infected cells with a low IC50 compared to control uninfected cells. The effects of alsterpaullone were associated with suppression of cdk2 and cyclin expression. Combining both alsterpaullone and r-roscovitine (cyc202) in treatment exhibited even stronger inhibitory activities in HIV-1 infected PBMCs.