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Cyclin-dependent kinases as cellular targets for antiviral drugs
1Department of Biochemistry, Signal Transduction Research Group, University of Alberta, 315C Heritage Medical Research Center, Edmonton, Alberta T6G 2S2, Canada. luis.schang@ualberta.ca
Abstract:
Cyclin-dependent kinases (cdks) are required for replication of viruses that replicate only in dividing cells, such as adeno- and papillomaviruses. Recently, cdks have been shown to be required also for replication of viruses that can replicate in non-dividing cells, such as HIV-1 and herpes simplex virus types 1 and 2 (HSV-1 and -2). In these experiments, pharmacological cdk inhibitors (PCIs) were shown to have potent antiviral activity in vitro against HIV-1, HSV-1 and -2, human cytomegalovirus, varicella-zoster virus, and to inhibit specific functions of other viruses. Since two PCIs, flavopiridol and roscovitine, are proving to be non-toxic in human clinical trials against cancer, PCIs may be useful as antivirals. As significant advantages, PCIs are active in vitro against many viruses, including drug-resistant strains of HIV-1 and HSV-1, and mutant strains of HIV-1 or HSV-1 resistant to PCIs have not been identified in spite of intense efforts. Furthermore, the antiviral effects of a PCI and a conventional antiviral drug are additive. The aetiopathogenesis of several diseases, such as Kaposi's sarcoma, HPV-induced cervical carcinoma and HIV-associated nephropathy (HIVAN), among others, includes replication or expression of proteins by viruses that require cdks. Thus, PCIs could target both the aetiological agent (the virus) and the pathogenic mechanisms (cell replication). Two important questions regarding the antiviral activities of PCIs are the focus of current research efforts, (i) the identity of the specific cdks that mediate the antiviral activities of PCIs, and (ii) whether PCIs have antiviral activity in vivo at non-toxic doses.
Insights
Pharmacological CDK inhibitors show potent antiviral activity against a wide range of viruses, including drug-resistant strains. These inhibitors may offer a novel therapeutic strategy for viral infections by targeting both the virus and host cell replication.
Area of Science:
- Virology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDKs) are essential for the replication of viruses in dividing cells.
- Recent findings indicate CDKs are also crucial for viruses replicating in non-dividing cells, such as HIV-1 and herpesviruses.
- Pharmacological CDK inhibitors (PCIs) have demonstrated potent in vitro antiviral activity.
Purpose of the Study:
- To investigate the potential of PCIs as broad-spectrum antiviral agents.
- To evaluate the efficacy of PCIs against various viruses, including drug-resistant strains.
- To explore the dual action of PCIs in targeting viral replication and pathogenic mechanisms.
Main Methods:
- In vitro testing of PCIs against multiple viral infections.
- Assessment of PCI activity against drug-resistant and mutant viral strains.
- Evaluation of the additive effects of PCIs with conventional antiviral drugs.
Main Results:
- PCIs exhibit potent in vitro antiviral activity against HIV-1, HSV-1, HSV-2, human cytomegalovirus, and varicella-zoster virus.
- PCIs are effective against drug-resistant strains of HIV-1 and HSV-1.
- No resistant viral strains to PCIs have been identified despite extensive efforts.
- Antiviral effects of PCIs are additive to those of conventional antiviral drugs.
Conclusions:
- PCIs represent a promising class of antiviral agents with broad-spectrum activity.
- PCIs may offer a novel therapeutic approach for viral diseases, including those caused by drug-resistant viruses.
- Further research is needed to identify specific CDKs involved and to confirm in vivo efficacy at non-toxic doses.