Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

摘要: Viral lethal mutagenesis is a strategy whereby the innate immune system or mutagenic pool nucleotides increase error rate of viral replication above catastrophe limit. Lethal has been proposed as mechanism for several antiviral compounds, including drug candidate 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212), which causes A-to-G and G-to-A mutations in HIV genome, both tissue culture positive patients undergoing KP1212 monotherapy. This work explored molecular mechanism(s) underlying mutagenicity KP1212, specifically whether tautomerism, previously hypothesis, could explain biological consequences this nucleoside analog. Establishing tautomerism nucleic acid bases under physiological conditions challenging because lack sensitive methods. study investigated using an array spectroscopic, theoretical, chemical biology approaches. Variable temperature NMR 2D infrared spectroscopic methods demonstrated that existed broad ensemble interconverting tautomers, among enolic forms dominated. The properties were determined empirically by vitro vivo single-stranded vector containing single KP1212. It was found paired with A (10%) G (90%), accord clinical observations. Moreover, mutation frequency sufficient pushing population over its limit, observed before cell studies. Finally, model correlates tautomeric distribution solution.