title: Pharmacological cyclin-dependent kinase inhibitors inhibit replication of wild-type and drug-resistant strains of herpes simplex virus and human immunodeficiency virus type 1 by targeting cellular, not viral, proteins.
abstract: Pharmacological cyclin-dependent kinase (cdk) inhibitors (PCIs) block replication of several viruses, including herpes simplex virus type 1 (HSV-1) and human immunodeficiency virus type 1 (HIV-1). Yet, these antiviral effects could result from inhibition of either cellular cdks or viral enzymes. For example, in addition to cellular cdks, PCIs could inhibit any of the herpesvirus-encoded kinases, DNA replication proteins, or proteins involved in nucleotide metabolism. To address this issue, we asked whether purine-derived PCIs (P-PCIs) inhibit HSV and HIV-1 replication by targeting cellular or viral proteins. P-PCIs inhibited replication of HSV-1 and -2 and HIV-1, which require cellular cdks to replicate, but not vaccinia virus or lymphocytic choriomeningitis virus, which are not known to require cdks to replicate. P-PCIs also inhibited strains of HSV-1 and HIV-1 that are resistant to conventional antiviral drugs, which target viral proteins. In addition, the anti-HSV effects of P-PCIs and a conventional antiherpesvirus drug, acyclovir, were additive, demonstrating that the two drugs act by distinct mechanisms. Lastly, the spectrum of proteins that bound to P-PCIs in extracts of mock- and HSV-infected cells was the same. Based on these observations, we conclude that P-PCIs inhibit virus replication by targeting cellular, not viral, proteins.
authors.affiliation: University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. luis.schang@ualberta.ca
authors.forename: Luis M
authors.initials: LM
authors.lastname: Schang
authors.forename: Andrew
authors.initials: A
authors.lastname: Bantly
authors.forename: Marie
authors.initials: M
authors.lastname: Knockaert
authors.forename: Farida
authors.initials: F
authors.lastname: Shaheen
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Michael H
authors.initials: MH
authors.lastname: Malim
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Priscilla A
authors.initials: PA
authors.lastname: Schaffer
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002522:Chlorocebus aethiops; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024882:Drug Resistance, Viral / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011687:Purines; D014764:Viral Proteins; C113584:purvalanol B; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases; D000225:Adenine