DNA polymerases as therapeutic targets.
Numerous pathological states, including cancer, autoimmune diseases, and viral/bacterial infections, are often attributed to uncontrollable DNA replication. Inhibiting this essential biological process provides an obvious therapeutic target against these diseases. A logical target is the DNA polymerase, the enzyme responsible for catalyzing the addition of mononucleotides to a growing polymer using a DNA or RNA template as a guide for directing each incorporation event. This review provides a summary of therapeutic agents that target polymerase activity. A discussion of the biological function and mechanism of polymerases is first provided to illustrate the strategy for therapeutic intervention as well as the rational design of various nucleoside analogues that inhibit various polymerases associated with viral infections and cancer. The development of nucleoside and non-nucleoside inhibitors as antiviral agents is discussed with particular emphasis on their mechanism of action, structure-activity relationships, toxicity, and mechanism of resistance. In addition, commonly used anticancer agents are described to illustrate the similarities and differences associated with various nucleoside analogues as therapeutic agents. Finally, new therapeutic approaches that include the inhibition of selective polymerases involved in DNA repair and/or translesion DNA synthesis as anticancer agents are discussed.
Berdis
Anthony J
AJ
Department of Pharmacology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA. ajb15@case.edu
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D004259:DNA-Directed DNA Polymerase