Cdk inhibitory nucleoside analogs prevent transcription from viral genomes.
Targeting viral proteins has lead to many successful antivirals. Yet, such antivirals rapidly select for resistance, tend to be active against only a few related viruses, and require previous characterization of the target proteins. Alternatively, antivirals may be targeted to cellular proteins. Replication of many viruses requires cellular CDKs and pharmacological CDK inhibitors (PCIs), such as the purine-based roscovitine (Rosco), are proving safe in clinical trials against cancer. Rosco inhibits replication of wild-type or (multi-)drug resistant HIV, HCMV, EBV, VZV, and HSV-1 and 2. However, the antiviral mechanisms of purine PCIs remain unknown. Our objective is to characterize these mechanisms using HSV as a model We have shown that Rosco prevents initiation of transcription from viral, but not cellular, genomes. This inhibition is promoter independent, but genome dependent, and requires no viral proteins. This is a novel antiviral mechanism and a previously unknown activity for purine PCIs.
Schang
L M
LM
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. luis.schang@ualberta.ca
Coccaro
E
E
Lacasse
J J
JJ
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D016679:Genome, Viral; D006801:Humans; D008956:Models, Chemical; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000737:chemistry / Q000494:pharmacology; D000077546:Roscovitine; D014158:Transcription, Genetic; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases