Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2'-deoxycytidine
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Li-2014-Tautomerism provides.pdf
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Author(s)
Li, Deyu
Fedeles, Bogdan I.
Singh, Vipender
Peng, Chunte Sam
Silvestre, Katherine J.
Simi, Allison K.
Simpson, Jeffrey H.
Essigmann, John M.
Tokmakoff, Andrei
Date Issued
July 2014
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences (U.S.)
Citation
Li, Deyu, Bogdan I. Fedeles, Vipender Singh, Chunte S. Peng, Katherine J. Silvestre, Allison K. Simi, Jeffrey H. Simpson, Andrei Tokmakoff, and John M. Essigmann. “Tautomerism Provides a Molecular Explanation for the Mutagenic Properties of the Anti-HIV Nucleoside 5-Aza-5,6-Dihydro-2’-Deoxycytidine.” Proceedings of the National Academy of Sciences 111, no. 32 (July 28, 2014): E3252–E3259.
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Center for Environmental Health Sciences
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
https://doi.org/10.1073/pnas.1405635111
