Exploring Flexible Purine Nucleobase Recognition by Biological Targets

Abstract

FDA approved nucleos(t)ide analogue inhibitors are increasingly plagued by the rapid loss of efficacy due to the diseases' ability to develop resistance. Consequently, the development of novel drugs that work through alternative modes of action are needed. The Seley-Radtke laboratory is focused on synthesizing nucleos(t)ide analogues endowed with additional flexibility in the nucleobase that may aid in circumventing point mutations associated with resistance mechanisms. In addition to retaining the hydrogen bonding and aromatic character required for binding site recognition, flexible purine nucleosides, termed "fleximers,” possess several key advantages over normal nucleosides, notably the ability to adapt to a flexible enzyme binding site and possible mutations. To test their effectiveness, we have synthetically coupled these modified bases to clinically relevant 2'-fluorinated sugars. In addition, we are working to enzymatically couple fleximer bases to ribose or deoxyribose.