Abstracto

Purine and nonpurine pharmacological CDK inhibitors target initiation of viral transcription

Jonathan J Lacasse, Veronic MI Provencher, Matthew D Urbanowski and Luis M Schang

Background: Antiviral drugs that target viral proteins are very successful but have certain limitations. Consequently, cellular proteins have begun to be considered as potential targets for novel antivirals. Cyclin-dependent kinases (CDKs) are arguably the cellular proteins best studied as potential targets. Several pharmacological CDK inhibitors (PCIs) have antiviral activity against wild-type or drug-resistant strains of HIV, human cytomegalovirus, herpes simplex virus (HSV), Epstein–Barr virus, varicella-zoster virus, Kaposi’s sarcoma herpesvirus, and human T-cell leukemia virus. Some PCIs such as roscovitine are apparently well tolerated and are scheduled to enter clinical trials as antivirals in 2005. However, the antiviral mechanisms of PCIs remain incompletely characterized, and PCIs with different molecular specificities may inhibit different viral functions. Objective: To evaluate whether PCIs with different molecular specificities target common viral functions. Methods: We evaluated the activities of structurally unrelated PCIs against a single model virus, HSV, in primary and immortalized fibroblasts. We tested whether roscovitine, flavopiridol, aloisine, and DRB, which preferentially inhibit different subsets of CDKs, inhibit HSV replication, transcription, or gene expression. Results: Aloisine was effective only in primary fibroblasts. Roscovitine, DRB, and to a lesser extent flavopiridol, inhibited HSV replication at lower concentrations in primary than in immortalized fibroblasts. These PCIs inhibited initiation of HSV transcription and accumulation of a viral protein into replication compartments. Flavopiridol also inhibited HSV transcription elongation. Conclusions: Structurally unrelated PCIs have common antiviral targets, although targets unique to certain PCIs also exist. We have identified two novel functional targets for antivirals, initiation of viral transcription and subcellular localization of viral proteins.