Chemical stabilization of unnatural nucleotide triphosphates for the in vivo expansion of the genetic alphabet

A.W. Feldman, V.T. Dien, F.E. Romesberg, J. Am. Chem. Soc. (2017) 139:2464–2467.
pubpic2017feldmanWe report the synthesis and evaluation of unnatural triphosphates with their β,γ-bridging oxygen replaced with a difluoromethylene moiety, yielding dNaMTPCF2 and dTPT3TPCF2. We find that although dNaMTPCF2 cannot support in vivo replication, likely due to poor polymerase recognition, dTPT3TPCF2 can, and moreover, its increased stability can contribute to increased UBP retention. The results demonstrate the promise of a chemical approach to SSO optimization.