Addressing the selectivity and toxicity of antiviral nucleosides

Feng, Joy Y

Nucleoside analogs were first studied as antimetabolites in the 1950s by George Hitchings and Gertrude Elion. 1 Their work led to the discovery of treatments for leukemia, gout, hyperuricemia, and parasitic protozoan infection, as well as an immunosuppressant for organ transplant. These efforts paved the way for the discovery of a series of nucleoside analogs as antitumor agents in the 1970s, some of which, such as ara-C and gemcitabine (Figure 1 ), are still in use today. 2, 3 Many of these antitumor nucleoside analogs showed antiviral activity, but none of them possessed an adequate clinical safety profile for antiviral use until Acyclovir (Figure 1 ) was discovered for the treatment of herpes simplex virus (HSV) infection, a breakthrough that started a new era in antiviral therapy. 1 Acyclovir's remarkable safety profile stemmed from two properties: (1) activation of the compound to its monophosphate (MP) only occurs in virus-infected cells, since this process relies on a viral thymidine kinase; and (2) acyclovir 5'-triphosphate (TP) selectively inhibits viral DNA polymerase over host DNA polymerase a. 4 Follow on generations of HSV nucleoside antivirals (penciclovir and ganciclovir, Figure 1 ) and prodrugs were developed to improve potency and resistance profiles. 5 The HIV/AIDS epidemic in the 1980s presented unprecedented demand for effective antivirals.