The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold

Abstract

This is the first of two invited articles reviewing the development of nucleoside-analogue antiviral drugs, written for a target audience of virologists and other non-chemists, as well as chemists who may not be familiar with the field. Rather than providing a simple chronological account, we have examined and attempted to explain the thought processes, advances in synthetic chemistry and lessons learned from antiviral testing that led to a few molecules being moved forward to eventual approval for human therapies, while others were discarded. The present paper focuses on early, relatively simplistic changes made to the nucleoside scaffold, beginning with modifications of the nucleoside sugars of Ara-C and other arabinose-derived nucleoside analogues in the 1960's. A future paper will review more recent developments, focusing especially on more complex modifications, particularly those involving multiple changes to the nucleoside scaffold. We hope that these articles will help virologists and others outside the field of medicinal chemistry to understand why certain drugs were successfully developed, while the majority of candidate compounds encountered barriers due to low-yielding synthetic routes, toxicity or other problems that led to their abandonment.

In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain)

“…3,4 Dihydropyrimidinones (DHPMs) are implicated in a wide range of biological activities. Pyrimidone derivatives are already being used against viral infections (Phucho et al, 2009;Wierenga et al, 1985;Skulnick et al, 1985;Sharma et al, 2014;Seley-Radtke et al, 2018). The pyrimidone nucleus is a core component of many of the anti-retroviral drugs (Sharma et al, 2014).…”

Selected nucleos(t)ide-based prescribed drugs and their multi-target activity

“…Nucleos(t)ide analogues are much more structurally diverse than their naturally occurring counterparts (Seley-Radtke and Yates, 2018;Yates and Seley-Radtke, 2019). Modifications may be introduced in the nucleobase, the sugar moiety or the phosphate residue.…”

Keto‐Enol Tautomerism in Nucleobase‐Substituted Aldols

“…During the last decades, many nucleotide analogues have been synthesised and their biological activities tested . The main therapeutic application of this family of compounds is in the field of antiviral agents, counting at the present with more than 30 drugs approved for numerous targets such as hepatitis, HIV and herpes virus infections ,. Among these analogues, acyclic nucleosides (ANs) exhibit enhanced chemical and metabolic stability, acting mainly as chain terminators during DNA or RNA biosynthesis.…”

“…[1] The main therapeutic application of this family of compounds is in the field of antiviral agents, counting at the present with more than 30 drugs approved for numerous targets such as hepatitis, HIV and herpes virus infections. [2,3] Among these analogues, acyclic nucleosides (ANs) exhibit enhanced chemical and metabolic stability, acting mainly as chain terminators during DNA or RNA biosynthesis. The first known member of this family, acyclovir, displays extremely low toxicity for normal cells and a strong inhibitory activity against herpes simplex virus (HSV) being today the main drug for the treatment of this infection.…”