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.