Two-dimensional IR spectroscopy of the anti-HIV agent KP1212 reveals protonated and neutral tautomers that influence pH-dependent mutagenicity
Abstract
The anti-HIV drug KP1212 was designed to intentionally increase the mutation rate of HIV, thereby causing viral population collapse. Its mutagenicity and thus antiviral activity was proposed to be the result of tautomerization. We used 2D IR spectroscopy to identify rapidly interconverting tautomers under physiological conditions. The traditionally rare enol-imino tautomer for nucleobases was found to be the major species for KP1212, providing a structural support for the tautomer hypothesis. We further found that KP1212 is significantly protonated at physiological pH with a pKa of 7. The protonated KP1212 was shown to be mutagenic, revealing a bimodal mutagenic property of KP1212. The results could prove instrumental in developing the next-generation antiviral treatments.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- March 2015
- DOI:
- 10.1073/pnas.1415974112
- Bibcode:
- 2015PNAS..112.3229P