Title | Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2'-deoxycytidine. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Li D, Fedeles BI, Singh V, Peng CSam, Silvestre KJ, Simi AK, Simpson JH, Tokmakoff A, Essigmann JM |
Journal | Proc Natl Acad Sci U S A |
Volume | 111 |
Issue | 32 |
Pagination | E3252-9 |
Date Published | 2014 Aug 12 |
ISSN | 1091-6490 |
Keywords | Anti-HIV Agents, Azacitidine, Bacteriophage M13, Base Pairing, Deoxycytidine, Genome, Viral, HIV, Humans, Isomerism, Magnetic Resonance Spectroscopy, Models, Chemical, Mutagens, Spectrophotometry, Infrared, Virus Replication |
Abstract | Viral lethal mutagenesis is a strategy whereby the innate immune system or mutagenic pool nucleotides increase the error rate of viral replication above the error catastrophe limit. Lethal mutagenesis has been proposed as a mechanism for several antiviral compounds, including the drug candidate 5-aza-5,6-dihydro-2'-deoxycytidine (KP1212), which causes A-to-G and G-to-A mutations in the HIV genome, both in tissue culture and in HIV positive patients undergoing KP1212 monotherapy. This work explored the molecular mechanism(s) underlying the mutagenicity of KP1212, and specifically whether tautomerism, a previously proposed hypothesis, could explain the biological consequences of this nucleoside analog. Establishing tautomerism of nucleic acid bases under physiological conditions has been challenging because of the lack of sensitive methods. This study investigated tautomerism using an array of spectroscopic, theoretical, and chemical biology approaches. Variable temperature NMR and 2D infrared spectroscopic methods demonstrated that KP1212 existed as a broad ensemble of interconverting tautomers, among which enolic forms dominated. The mutagenic properties of KP1212 were determined empirically by in vitro and in vivo replication of a single-stranded vector containing a single KP1212. It was found that KP1212 paired with both A (10%) and G (90%), which is in accord with clinical observations. Moreover, this mutation frequency is sufficient for pushing a viral population over its error catastrophe limit, as observed before in cell culture studies. Finally, a model is proposed that correlates the mutagenicity of KP1212 with its tautomeric distribution in solution. |
DOI | 10.1073/pnas.1405635111 |
Alternate Journal | Proc Natl Acad Sci U S A |
PubMed ID | 25071207 |
PubMed Central ID | PMC4136561 |
Grant List | R37 CA080024 / CA / NCI NIH HHS / United States P01 CA26731 / CA / NCI NIH HHS / United States T32 ES007020 / ES / NIEHS NIH HHS / United States P30 ES002109 / ES / NIEHS NIH HHS / United States P01 CA026731 / CA / NCI NIH HHS / United States P41 EB015871 / EB / NIBIB NIH HHS / United States |
Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2'-deoxycytidine.
Submitted by Vipender Singh on
2 Comments
* These authors contributed
Submitted by Vipender Singh on
* These authors contributed equally to the work (Order of names in the manuscript:, Li D*, Fedeles BI*, Singh V*, Peng CSam*
- http://newsoffice.mit.edu/2014/forced-mutations-doom-hiv-0728
Comments
Submitted by Vipender Singh on
* These authors contributed equally (order in manuscript: Li D*, Fedeles BI*, Singh V*, Peng CSam*
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