| Summary: | Thesis: S.B. in Chemistry and Biology, Massachusetts Institute of Technology, Department of Chemistry, 2014. === Cataloged from PDF version of thesis. === Includes bibliographical references (pages 34-35). === The high mutation rate of HIV makes treatment of HIV/AIDS difficult, as the virus can develop resistance to existing therapeutics. A novel antiviral nucleoside analog, 5-Aza-5,6-dihydro-2'- deoxycytidine (KP1212), employs the mechanism of lethal mutagenesis to avoid the problem of drug resistance and use the virus's high mutation rate against it. KP1212 is incorporated into DNA by HIV reverse transcriptase (RT) but mispairs with adenine instead of guanine, increasing the rate of purine transitions. This increased mutation rate can push HIV over its error catastrophe limit, resulting in viral ablation. To understand how KP1212 induces lethal mutagenesis, VT NMR studies were conducted on KP1212. These experiments revealed that the enol tautomers of KP1212 are more prevalent than the keto tautomers, in contrast to native 2'-deoxycytidine (dC) which is predominately found in the keto-amino tautomer. The enol tautomers are able to base-pair with adenine, causing the increase rate of purine transitions observed in tissue culture and in clinical trials of KP1212. The distribution of KP1212 tautomers measured by VT NMR support tautomerization as the molecular mechanism for KP1212-induced lethal mutagenesis. VT NMR experiments on a variety of known mutagenic nucleoside analogs found that many of them, including 5-aza-2'-deoxycytidine (decitabine), did not show multiple tautomers and thus had other molecular mechanisms behind their mutagenicity. This suggested that breaking the aromaticity of the nucleobase in KP1212 had a significant effect on the distribution of tautomers. To understand this structural change, the hydrogenated nucleoside analog 5,6-dihydro-2'- deoxycytidine (DHdC) was synthesized via continuous-flow hydrogenation of dC. VT NMR studies show multiple tautomers for DHdC, demonstrating that hydrogenated nucleoside analogs could provide a variety of untested lethal mutagens for further study. === by Katherine J. Silvestre. === S.B. in Chemistry and Biology
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