Predicting Off-Target Effects of Therapeutic Antiviral Ribonucleosides: Inhibition of Mitochondrial RNA Transcription

Therapeutic ribonucleoside inhibitors have been recognized as one of the most promising classes of antiviral compounds currently being developed to treat RNA virus infections. The ability of antiviral ribonucleosides to be incorporated in vivo will depend on the sizes of the intracellular antiviral ribonucleoside triphosphate pool and natural ribonucleoside triphosphate pool with which the analogue competes. It has long been recognized that the human mitochondrial DNA polymerase has been an "off-target" of nucleoside reverse transcriptase inhibitors (NRTIs) used for the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. The biochemical tools used to study substrate utilization by mitochondrial RNA polymerase (POLRMT) in vitro were recently developed. These advancements have allowed the determination of the utilization of antiviral ribonucleoside triphosphates by POLRMT and so predicting unwanted "off-target" inhibition of mitochondrial transcription. The limited diversity of both the nuclear genome and mtDNA can essentially desensitize cells to changes in proper mitochondrial function.