DNA nucleoside analogs, KP-1212 and 5-hydroxy-2'-deoxycytidine, are drug candidates for the treatment of HIV/AIDS via lethal mutagenesis (viral decay acceleration) mechanism. KP-1212 is currently in Phase II clinical trials because it can induce a significant increase in viral mutation frequency and make the virus unable to synthesize functional proteins. The mechanism of action believed to be responsible for lethal mutagenesis is tautomerization of the nucleoside analog, which allows the nucleoside to base-pair with more than one complementary base. NMR spectroscopy can be used to identify the tautomeric forms of these nucleosides and the ratios of these tautomers. 1D 1H, 13C, 2D homonuclear (1H-1H COSY, NOESY), heteronuclear (1H-13C HSQC, HMBC), and variable temperature experiments are used to assign chemical shifts and characterize enol-keto and amino-imino tautomers of these nucleosides. By evaluating the tautomerization of multiple nucleoside analogs, we rationalize the molecular mechanism of lethal mutagenesis as a novel drug design principle.

NMR study on the tautomerism of anti-HIV nucleoside analogs

243rd National Meeting (2012)

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