Design and Synthesis of Flex AT-527 as a Potential Antiviral Therapeutic

Abstract

One outcome from the COVID-19 pandemic was the realization that we desperately need access to broad-spectrum antivirals that can be readily stockpiled and distributed to quickly treat infected individuals. Nucleoside analogues are sought after for this reason, as they have shown significant activity as a class of antivirals for decades. The Seley-Radtke group has focused on modifying the bicyclic purine base moiety of nucleoside analogues by incorporating a carbon-carbon single bond between the two heterocyclic components, endowing the nucleobase with flexibility. As a result, the fleximers can adopt a variety of favorable conformations thereby allowing the compound to exhibit potent antiviral activity not seen in the rigid-parent nucleoside. In addition, this allows for the ability to overcome antiviral resistance, as well as to be recognized by various viral enzymes, resulting in significant activity against a wide variety of viruses. AT-527 is a nucleoside analogue originally designed to treat Hepatitis C Virus (HCV), that has shown activity against SARS-CoV-2 and other viruses. The aim of this project is to incorporate the fleximer technology into the AT-527 scaffold, thereby potentially expanding its biological scope. Computational docking studies were carried out to explore the binding potential for a series of AT analogues, as well as to guide future SAR studies. The synthesis of the parent Flex-AT-527 was completed in ten steps, with each step having fair to good yields. The results of this project are reported herein.