Targeting structural dynamics of the RNA-dependent RNA polymerase for anti-viral strategies

• RNA-dependent RNA polymerases (RdRps) are important anti-viral targets.
• Internal motions are coordinated and conserved in RdRps.
• Interfering with these motions disrupts RdRp and virus function.
• RdRp variants with altered dynamics serve as frameworks for anti-viral strategies.
• Alternatively, small molecules may upset crucial RdRp motions.

The RNA-dependent RNA polymerase is responsible for genome replication of RNA viruses. Nuclear magnetic resonance experiments and molecular dynamics simulations have indicated that efficient and faithful polymerase function requires highly coordinated internal protein motions. Interference with these motions, either through amino acid substitutions or small molecule binding, can disrupt polymerase and virus function. In particular, these studies have pointed toward highly conserved structural elements, like the motif-D active-site loop, that can be modified to generate polymerases with desired properties. Viruses encoding engineered polymerases might serve as live, attenuated vaccine strains. Further elucidation of polymerase structural dynamics will also provide new avenues for anti-viral drug design.