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Technology

This technology can tune the mutagenicity of nucleosides analogs by changing the pKa of the molecule. In its active form, KP1212 is a cytidine nucleotide analog that causes G-to-A mutations. These inventors demonstrated that the KP1212 mutagenic capacity is highly dependent on pH. At physiological pH KP1212 is only marginally mutagenic, resulting in G-to-A mutation only about 10% of the time. Reducing pH in vitro significantly increases its mutagenic capacity, which demonstrates that the protonated form of KP1212 is more highly mutagenic. Additionally, this finding suggests that tuning the pKa of KP1212 to be protonated at physiological pH could greatly increase its mutagenic efficiency. Importantly, these results also indicate that tuning the pKa of nucleoside analogs could be a more general mechanism for changing the mutagenic properties of nucleoside analogs.