Flex-Nucleosides: A Strategic Approach to Antiviral Therapeutics

Abstract

One of the most common classes of drugs is nucleoside analogues, which have long served as a cornerstone for antiviral, antiparasitic, and anticancer treatments. This is due to their close resemblance to the naturally occurring nucleosides found in many biological processes. In terms of antiviral drug design, typically viral proteins or cellular proteins are targeted. Each has its pros and cons; however, both carry the risk of the development of drug resistance, making it imperative that novel and more effective antivirals are developed. This chapter will focus on a specific class of shaped-modified nucleoside analogues called fleximers. These flexible nucleoside analogues possess a split purine ring system, which endows flexibility to the nucleobase scaffold. This flexibility has been shown to be beneficial for increased antiviral activity but also results in broad-spectrum antiviral activity as well as the potential to overcome point mutations related to viral drug resistance. For over two decades now, the fleximer technology has been applied to numerous nucleoside analogues and has led to potent, broad-spectrum activity against a wide array of viruses including flaviviruses, filoviruses, and coronaviruses, among others. Their history and development, the various synthetic routes to realize them, and some of the biological data obtained to date for the fleximers will be discussed within this chapter.