Addressing the selectivity and toxicity of antiviral nucleosides

Feng, Joy Y

gure 1 ) were all liver-targeting nucleotide prodrugs and the administration of PSI-938 and VX-135 resulted in liver toxicity, 27,28 BMS-986094 showed cardiovascular and renal toxicity. 29 It is worthwhile mentioning that antiviral nucleosides could also exert toxicity through disruption of natural NTP pools. AZT only showed modest inhibition of mitochondrial DNA polymerase 7 but is a competitive inhibitor of thymidine kinase 2-catalized phosphorylation of thymidine to TMP. 30 Ribavirin is a poor substrate for mitochondrial RNA polymerase, 22 but it reduces the size of the guanosine triphosphate (GTP) pool via inhibition of inosine MP dehydrogenase. 31 As one might expect, there are many possible ways that a nucleoside/tide analog can elicit toxicity that are still beyond our knowledge. In this review, we focus on the host polymerase mechanism-based toxicity and summarize different biochemical and cellular assays to evaluate potential toxicity liabilities, and the strength and limitations of each method.