Nucleosides and emerging viruses: A new story

Abstract

With several US Food and Drug Administration (FDA)-approved drugs and high barriers to resistance, nucleoside and nucleotide analogs remain the cornerstone of antiviral therapies for not only herpesviruses, but also HIV and hepatitis viruses (B and C); however, with the exception of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which vaccines have been developed at unprecedented speed, there are no vaccines or small antivirals yet available for (re)emerging viruses, which are primarily RNA viruses. Thus, herein, we present an overview of ribonucleoside analogs recently developed and acting as inhibitors of the viral RNA-dependent RNA polymerase (RdRp). They are new lead structures that will be exploited for the discovery of new antiviral nucleosides.

Keywords: (Re)emerging RNA viruses; Antiviral therapy; Broad-spectrum antiviral agents; Nucleoside analogues; RNA-dependent RNA polymerase (RdRp).

Figure 1

Chemical structures of antiviral nucleosides. This includes nucleoside analogs (IDU, AZT, D4T, L-dT, 3TC, FTC), carbocyclic nucleoside analogs (ABC and entecavir) and acyclic nucleoside phosphonates (PMEA, HPMPC, and PMPA) and their prodrugs [bis(POM)PMEA, bis(POC)PMPA, and tenofovir alafenamide].

Figure 2

Main mechanism of activation of antiviral nucleosides by various nucleoside and nucleotide kinases. After cell penetration, the nucleoside is converted by nucleoside kinases (dN kinases) to its monophosphate, then to the diphosphate by nucleoside monophosphate kinases (NMP kinases) and finally to the triphosphate by nucleotide diphosphate kinase (NDP kinases). Adapted from.

Figure 3

Examples of kinase bypass strategies applied to deliver antiviral nucleosides as their monophosphate prodrug analogs.

Figure 4

Relevant prodrugs, including ProTide technology, applied to marketed antiviral nucleosides.

Figure 5

Percentage similarity of RNA-dependent RNA polymerases of various RNA viruses. Adapted from. For definitions of abbreviations, please see the main text.

Figure 6

Structure of antiviral nucleosides inhibitors of RNA-dependent RNA polymerases of RNA viruses.