The Design, Synthesis, and Biological Evaluation of a Series of Acyclic Fleximer Nucleoside Antivirals

Replication is intrinsically involved in the lifecycle of all viruses, thus their survival relies on DNA or RNA polymerases. As a result, the polymerase is considered one of the most important targets for antiviral drug design. One of the most effective strategies in targeting this enzyme is through the use of nucleos(t)ide analogs. An area in which these analogs have yet to have impact is against the coronaviruses (CoVs), especially Severe Acute Respiratory Syndrome-CoV (SARS), and the newly discovered Middle East Respiratory Syndrome-CoV (MERS). Previously it was found that a "split base" guanosine analog (Flex-GTP) developed in our laboratory retained full potency against binding site mutations in guanosine fucose pyrophosphorylase (GFPP) due to interactions with secondary amino acid residues. Flex-G also served as an inhibitor of S-adenosylhomocysteine hydrolase, an adenosine-metabolizing enzyme. These observations strongly indicate that exploitation of conformational and positional flexibility in the nucleobase scaffold can be used as a powerful tool for developing drugs that can bind to atypical enzymes in biologically significant conformations.;In that regard, several series of fleximer analogs have shown promise in a number of therapeutic areas including cancer and parasites. This project encompasses the design, synthesis and evaluation of a new series of novel nucleoside analogs that combine the "fleximer" base modification with various modified sugars found in several FDA-approved antiviral nucleoside drugs, including the acyclic sugar found in Acyclovir. This scaffold led to potent biological activity against a number of viral targets, but most surprisingly, against the coronaviruses, with inhibitory concentrations for Flex-Acyclovir (and structurally related Flex-acyclic analogs) as low as 3.5 muM. This is the best activity profile for a nucleoside analog against coronaviruses observed to date. The results of these studies will be presented herein.