Inhibition of Viral RNA-Dependent RNA Polymerases by Nucleoside Inhibitors: An Illustration of the Unity and Diversity of Mechanisms

RNA-dependent RNA polymerase (RdRP) is essential for the replication and expression of RNA viral genomes. This class of viruses comprise a large number of highly pathogenic agents that infect essentially all species of plants and animals including humans. Infections often lead to epidemics and pandemics that have remained largely out of control due to the lack of specific and reliable preventive and therapeutic regimens. This unmet medical need has led to the exploration of new antiviral targets, of which RdRP is a major one, due to the fact of its obligatory need in virus growth. Recent studies have demonstrated the ability of several synthetic nucleoside analogs to serve as mimics of the corresponding natural nucleosides. These mimics cause stalling/termination of RdRP, or misincorporation, preventing virus replication or promoting large-scale lethal mutations. Several such analogs have received clinical approval and are being routinely used in therapy. In parallel, the molecular structural basis of their inhibitory interactions with RdRP is being elucidated, revealing both traditional and novel mechanisms including a delayed chain termination effect. This review offers a molecular commentary on these mechanisms along with their clinical implications based on analyses of recent results, which should facilitate the rational design of structure-based antiviral drugs.