Predicting Off-Target Effects of Therapeutic Antiviral Ribonucleosides

Inhibition of Mitochondrial RNA Transcription

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

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.

Original languageEnglish (US)
Title of host publicationMitochondrial Dysfunction Caused by Drugs and Environmental Toxicants
Publisherwiley
Pages407-417
Number of pages11
Volume1-2
ISBN (Electronic)9781119329725
ISBN (Print)9781119329701
DOIs
StatePublished - Feb 21 2018

Fingerprint

Ribonucleosides
Therapeutic Uses
Transcription
Antiviral Agents
Viruses
Mitochondrial DNA
RNA Virus Infections
Reverse Transcriptase Inhibitors
Virus Diseases
DNA-Directed DNA Polymerase
DNA-Directed RNA Polymerases
Nucleosides
Hepatitis B virus
Genes
mitochondrial RNA
HIV
Genome
RNA
Substrates
triphosphoric acid

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Arnold, Jamie Jon ; Cameron, Craig Eugene. / Predicting Off-Target Effects of Therapeutic Antiviral Ribonucleosides : Inhibition of Mitochondrial RNA Transcription. Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants. Vol. 1-2 wiley, 2018. pp. 407-417
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Predicting Off-Target Effects of Therapeutic Antiviral Ribonucleosides : Inhibition of Mitochondrial RNA Transcription. / Arnold, Jamie Jon; Cameron, Craig Eugene.

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants. Vol. 1-2 wiley, 2018. p. 407-417.

Research output: Chapter in Book/Report/Conference proceedingChapter

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AB - 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.

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