Targeting SARS-CoV-2 RNA: Insights for RNA-Directed Drug Discovery

Traditional pharmacology fights virus infections by targeting proteins including enzymes, receptors, and structural proteins to break up the viral machinery. Nucleic acid-targeting therapies, on the other hand, can act directly on the genetic code of viruses, blocking their replication or translation in host cells. Coronaviruses and HIV are examples of RNA viruses that use a process called -1 programmed ribosomal frameshifting (-1 PRF) to produce their viral proteins. In this process, the translating ribosome is forced to shift into the alternative reading frame, replicating mRNA in the wrong order. Using small-molecule compounds to block this mechanism could be a promising way to neutralize such viruses.

It is difficult to experimentally study the interactions between RNA and a drug candidate to understand where the drug binds and how it changes the shape of the viral RNA. I will discuss how Molecular Dynamics simulations are used to explore the conformational dynamics of mRNA structural elements and to investigate what happens when an antiviral agent binds to it. Additionally, I will show how the quantum-chemical orbital interaction analysis we developed, called Through-Space/Through-Bond Energy Decomposition Analysis (TS/TB-EDA), reveals which RNA nucleotides, at the atomic level, are critical for binding. This molecular modelling approach reveals strategies for targeting structured RNA elements — a crucial step toward expanding the arsenal of RNA-targeting therapeutics for future pandemics.