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Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides
dc.contributor.author | Arnold, Jamie J. | |
dc.contributor.author | Sharma, Suresh D. | |
dc.contributor.author | Feng, Joy Y. | |
dc.contributor.author | Ray, Adrian S. | |
dc.contributor.author | Smidansky, Eric D. | |
dc.contributor.author | Kireeva, Maria L. | |
dc.contributor.author | Cho, Aesop | |
dc.contributor.author | Perry, Jason | |
dc.contributor.author | Vela, Jennifer E. | |
dc.contributor.author | Park, Yeojin | |
dc.contributor.author | Xu, Yili | |
dc.contributor.author | Tian, Yang | |
dc.contributor.author | Babusis, Darius | |
dc.contributor.author | Barauskus, Ona | |
dc.contributor.author | Peterson, Blake R. | |
dc.contributor.author | Gnatt, Averell | |
dc.contributor.author | Kashlev, Mikhail | |
dc.contributor.author | Zhong, Weidong | |
dc.contributor.author | Cameron, Craig E. | |
dc.date.accessioned | 2014-03-07T22:00:29Z | |
dc.date.available | 2014-03-07T22:00:29Z | |
dc.date.issued | 2012-11-15 | |
dc.identifier.citation | Arnold, J. J., Sharma, S. D., Feng, J. Y., Ray, A. S., Smidansky, E. D., Kireeva, M. L., … Cameron, C. E. (2012). Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides. PLoS Pathog, 8(11). http://dx.doi.org/10.1371/journal.ppat.1003030 | |
dc.identifier.uri | http://hdl.handle.net/1808/13163 | |
dc.description.abstract | Ribonucleoside analogues have potential utility as anti-viral, -parasitic, -bacterial and -cancer agents. However, their clinical applications have been limited by off target effects. Development of antiviral ribonucleosides for treatment of hepatitis C virus (HCV) infection has been hampered by appearance of toxicity during clinical trials that evaded detection during preclinical studies. It is well established that the human mitochondrial DNA polymerase is an off target for deoxyribonucleoside reverse transcriptase inhibitors. Here we test the hypothesis that triphosphorylated metabolites of therapeutic ribonucleoside analogues are substrates for cellular RNA polymerases. We have used ribonucleoside analogues with activity against HCV as model compounds for therapeutic ribonucleosides. We have included ribonucleoside analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents that are non-obligate chain terminators of the HCV RNA polymerase. We show that all of the anti-HCV ribonucleoside analogues are substrates for human mitochondrial RNA polymerase (POLRMT) and eukaryotic core RNA polymerase II (Pol II) in vitro. Unexpectedly, analogues containing 2′-C-methyl, 4′-methyl and 4′-azido substituents were inhibitors of POLRMT and Pol II. Importantly, the proofreading activity of TFIIS was capable of excising these analogues from Pol II transcripts. Evaluation of transcription in cells confirmed sensitivity of POLRMT to antiviral ribonucleosides, while Pol II remained predominantly refractory. We introduce a parameter termed the mitovir (mitochondrial dysfunction caused by antiviral ribonucleoside) score that can be readily obtained during preclinical studies that quantifies the mitochondrial toxicity potential of compounds. We suggest the possibility that patients exhibiting adverse effects during clinical trials may be more susceptible to damage by nucleoside analogs because of defects in mitochondrial or nuclear transcription. The paradigm reported here should facilitate development of ribonucleosides with a lower potential for toxicity. | |
dc.publisher | Public Library of Science | |
dc.rights | This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. | |
dc.rights.uri | https://creativecommons.org/publicdomain/zero/1.0/ | |
dc.subject | Adverse reactions | |
dc.subject | Antivirals | |
dc.subject | Mitochondria | |
dc.subject | Mitochondrial DNA | |
dc.subject | Nucleotides | |
dc.subject | Rna polymerase | |
dc.subject | Toxicity | |
dc.title | Sensitivity of Mitochondrial Transcription and Resistance of RNA Polymerase II Dependent Nuclear Transcription to Antiviral Ribonucleosides | |
dc.type | Article | |
kusw.kuauthor | Peterson, Blake R. | |
kusw.kudepartment | Medicinal Chemistry | |
kusw.oastatus | fullparticipation | |
dc.identifier.doi | 10.1371/journal.ppat.1003030 | |
kusw.oaversion | Scholarly/refereed, publisher version | |
kusw.oapolicy | This item meets KU Open Access policy criteria. | |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.