Design, Synthesis, and Biological Evaluation of Modified Acyclic Fleximer Nucleoside Analogues

Abstract

As the SARS-CoV-2 pandemic left lingering effects worldwide, it remains clear there is a need for the development of broad-spectrum antiviral therapeutics to not only help fight the pandemic at hand but help fight future pandemics to come. With this in mind nucleos(t)ides have had a rich history as antivirals. A commonly employed modification is the use of an acyclic sugar (lack of 2’ and/or 3’ carbons on the sugar moiety), such as that found in Acyclovir (ACV), an FDA-approved drug for herpes simplex virus or the FDA-approved drug Cidofovir (CDV) for CMV retinitis. Research in the Seley-Radtke group focuses on investigating nucleos(t)ide analogues known as “fleximers”, which feature a purine nucleobase “split” into its imidazole and pyrimidine moieties via a carbon-carbon single bond, thus introducing flexibility to the nucleobase. This novel design has endowed the fleximer analogues with potent activity not seen in the rigid parent nucleosides. Combining the acyclic sugar, with the fleximer technology produced a series of first-generation, doubly flexible Flex-ACV analogues. Some of these analogues have exhibited activity against filoviruses, flaviviruses, and coronaviruses. Given the broad-spectrum activity exhibited by these fleximers, optimization of previously synthesized Flex-ACV analogues was carried out for further investigation into the biological effects of these nucleosides. The first-generation Flex-ACV nucleosides were synthesized using modern organic chemistry techniques such as various cross-coupling methods, as well as microwave assisted chemistry. Synthesis of various monophosphate and triphosphate analogues allowed for elucidation of the metabolism and mechanism of action of the first-generation analogues. A new series of Flex-ACV analogues that feature a bond between carbon 5 of imidazole and carbon 5 of the pyrimidine moiety have been designed and synthesized. The newly designed analogues are of interest to compare them to the typical proximal fleximer design and evaluate their antiviral activity as well as the potential to reach new residues in a viral enzyme binding pocket. Overall, the flexible acyclic nucleosides continue to show broad-spectrum antiviral activity and have the potential to become an antiviral therapeutic.