Helicases as antiviral and anticancer drug targets.
In the cell, the unwinding of double-stranded polynucleotides is catalyzed by helicases that are present in all kingdoms of life from virus to man. Viruses, like all other organisms, synthesize their DNA or RNA genomes in a template-dependent manner. In addition to DNA or RNA polymerases, a helicase is therefore required to displace the single-stranded genome after replication, thus leading to the formation of progeny viral particles. In drug design against viral helicases, a number of viral helicase inhibitors have been developed and used in clinical studies. In humans, DNA helicases play essential roles in facilitating cellular DNA metabolisms including genome replication, DNA repair, recombination, transcription as well as telomere maintenance. The care-taker roles of helicases suggest that they might be suitable for targeting to prevent cell proliferation during carcinogenesis. Identifying helicase specific-inhibitors may lead to the development of drugs in the treatment of human cancers. In addition, some helicases such as BLM and WRN interact physically and functionally with telomerases and are involved in telomere maintenance. Hence, an antitumor therapy designed to interfere with both helicases and telomerases may be much more effective than the helicase or telomerase inhibitors alone. This review addresses these topics and discusses the design of antiviral and antitumoral agents based on the knowledge of structures and functions of helicases.
Xi
Xu Guang
XG
Laboratoire de Biotechnologies et Pharmacologie Génétique Appliquée CNRS UMR 8113, Ecole Normale Supérieure (ENS) Cachan, 94235 Cachan Cedex, France. xi@1bpa.ens-cachan.fr
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004265:DNA Helicases