JAC Advance Access published online on November 18, 2002
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkf227
© 2002 by The British Society for Antimicrobial Chemotherapy
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Review Article
1 Departments of Biochemistry and Medical Microbiology and
Immunology, Signal Transduction Research Group, University of Alberta,
315C Heritage Medical Research Center, Edmonton, Alberta T6G 2S2,
Canada
* Corresponding author. E-mail: luis.schang{at}ualberta.ca.
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.
Cyclin-dependent kinases as cellular targets for
antiviral drugs
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