Highly effective viral RdRP translocation hindrance by the remdesivir nucleotide.

Remdesivir inhibits viral RdRP translocation at least 100-fold more effectively than adenosine, significantly impacting the nucleotide addition cycle in enterovirus RdRP.

• Why it matters: Understanding how nucleoside analogs interfere with polymerase translocation can improve antiviral drug design, but direct, quantitative evidence has been lacking, limiting rational development.
• What they did: The study used X-ray crystallography, quench-flow kinetics, and molecular dynamics simulations to compare the translocation rates of RDV and adenosine in enterovirus RdRP, revealing a major slowdown caused by RDV.
• The result: Mutating serine417 to glycine reduces this translocation hindrance, yet RDV still alters the free-energy landscape, suggesting translocation interference as a promising strategy for broad-spectrum polymerase inhibition.