Comparison of the Old and New - Novel Mechanisms of Action for Anti-coronavirus Nucleoside Analogues

Abstract

Over the past two and a half years the world has seen a desperate scramble to find a treatment for SARS-CoV-2 and COVID. In that regard, nucleosides have long served as the cornerstone to antiviral treatments due to their resemblance to the naturally occurring nucleosides that are involved in numerous biological processes. Unlike other viruses however, it was found early on during the search for drugs to treat SARS-1 and later MERS, that the coronaviruses possess a unique repair enzyme, an exonuclease (ExoN)[3] which rendered nucleoside analogues useless, thus negating their use.[4] During the current outbreak however, as both well-known and new nucleoside analogues were investigated or reinvestigated as a possible cure for SARS-CoV-2, several novel and/or lesser-known mechanisms of action were uncovered. This review briefly describes these mechanisms.

Phenotypic Test of Benzo[4,5]imidazo[1,2-c]pyrimidinone-Based Nucleoside and Non-Nucleoside Derivatives against DNA and RNA Viruses, Including Coronaviruses

“…Nucleoside analogs (NAs) are considered a good choice for quick and efficient development of antiviral therapeutics. Most NAs inhibit viral replication through chain termination or lethal mutagenesis [6][7][8], but they can also affect the efficiency of the binding of a viral nucleic acid to polymerases and inhibit viral methyltransferases and a number of host cell enzymes that are essential for virus replication, such as those involved in nucleotide synthesis and RNA capping [9][10][11]. The efficacy and safety profiles of NAs have been extensively studied, and over 30 NAs have already been approved by the FDA [12,13].…”

“…Nucleoside analogs are derivatives of natural nucleosides with a modified sugar residue and/or nucleobase. Sugar modification has been extensively used to obtain viral polymerase inhibitors [7], but the potential of nucleobase modifications has been less explored. Modifications of nucleobases can be classified as follows: (1) nitrogen substitution and rearrangements in the heterocycle (aza and deaza derivatives), (2) side-chain substitution, (3) heterocycle splitting, and (4) nucleobases expansion (Figure 1).…”

How Much Potential Do Nucleoside Analogs Offer to Combat Human Corona Viruses?

“…These reviews have mainly mentioned either remdesivir or a very narrow group of NAs [19][20][21][22][23][24][25]. Particular emphasis has been on compounds with known mechanisms of action against SARS-CoV-2 (Figure 1) [26][27][28]. Although the susceptibility of HCoVs to a variety of NAs has been studied for over twenty years, only a few original publications have been included in a review discussing a relatively broad group of twenty-four NAs with micromolar activity against SARS-CoV, SARS-CoV-2 or MERS-CoV, and HCoV-NL63 [29].…”

“…These reviews have mainly mentioned either remdesivir or a very narrow group of NAs [19][20][21][22][23][24][25]. Particular emphasis has been on compounds with known mechanisms of action against SARS-CoV-2 (Figure 1) [26][27][28].…”