Addressing the selectivity and toxicity of antiviral nucleosides

Feng, Joy Y

In 1986, azidothymidine (AZT, zidovudine, Figure 1 ), a chain-terminating inhibitor of HIV-1 reverse transcriptase (RT), was approved, signifying the first step towards control of this devastating disease. The first generation of nucleoside analogs for HIV was efficacious, but these compounds also showed considerable toxicity, including cardiomyopathy (AZT, ddI, and ddC, Figure 1 ), peripheral neuropathy (d4T, ddI, and ddC), sensorineural deafness (ddC), lactic acidosis (AZT, ddI, and d4T), diabetes (ddI), and cytopenia (AZT). 6, 7 The toxicity of ddC and AZT was associated with inhibition of mitochondria DNA synthesis in cell culture [8] [9] [10] and in patient tissue samples. 11 Later on, detailed kinetic studies of HIV nucleosides using recombinant human mitochondrial DNA polymerase (Pol c) demonstrated the importance of selective inhibition of on-target HIV-1 RT over that of the off-target human Pol c. 7, 12 Unfortunately, this knowledge came 10 years too late to inform the 1993 Phase II clinical trial of FIAU in patients infected with HBV, where 7 out of 15 patients developed severe liver toxicity and lactic acidosis, and 5 of these patients died. 13 Followup biochemical, cellular, and in vivo studies showed that FIAU was readily incorporated into mitochondrial DNA, leading to a decrease in mtDNA abundance and thus rendering the mitochondria dysfunctional. 14, 15 The prevalence of mitochondrial toxicity associated with 2 0 -deoxy nucleoside analogs led to the FDA's recommendation to test drug candidates in a set of mitochondrial toxicity assays including Pol c inhibition, lactic acid formation, mitochondrial DNA content, and glucose utilization. 16 With the use of these tests, the second-generation antiviral nucleoside/tide analogs such as 3TC, FTC, and tenofovir were shown to be poor substrates of Pol c and demonstrated significantly improved clinical safety profiles.