Five years of progress on cyclin-dependent kinases and other cellular proteins as potential targets for antiviral drugs.
In 1997-1998, the pharmacological cyclin-dependent kinase (CDK) inhibitors (PCIs) were independently discovered to inhibit replication of human cytomegalovirus, herpes simplex virus type 1 and HIV-1. The results from small clinical trials against cancer were then suggesting that PCIs could be safe enough to be used clinically. It was thus hypothesized that PCIs could have the potential to be developed as novel antivirals targeting cellular proteins. Consequently, Antiviral Chemistry & Chemotherapy published in 2001 the first review on the potential of CDKs, and cellular proteins in general, as potential targets for antivirals. The viral functions inhibited by PCIs, or their cellular targets, were then just starting to be characterized. The antiviral spectrum of PCIs and their effects on viral disease were still mostly untested. Even their actual specificity was not yet completely characterized. In addition, cellular proteins were not accepted as valid targets for antivirals. Significant progress has been made in the last 5 years in understanding the antiviral activities of PCIs and the potential roles of cellular proteins in general as targets for antivirals. The first clinical trials of the antiviral activities of PCIs and other inhibitors of cellular protein kinases have now been scheduled. Herein, we review the progress made since the publication of the first review on PCIs as potential antiviral drugs and on CDKs, and cellular proteins in general, as potential targets for antiviral drugs. We also highlight the major issues that still need to be addressed before PCIs or other drugs targeting cellular proteins can be developed as clinical antivirals.
Schang
Luis M
LM
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada. luis.schang@ualberta.ca
St Vincent
Mireille R
MR
Lacasse
Jonathan J
JJ
D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003587:Cytomegalovirus / Q000187:drug effects / Q000201:enzymology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006561:Herpes Simplex / Q000188:drug therapy; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D018844:Cyclin-Dependent Kinases