Insights in the RSV L polymerase function and structure

Respiratory syncytial virus (RSV) continues to have a large medical and economic impact worldwide, mainly in infants, elderly, and immunocompromised patients. While several vaccines and prophylactic antibodies are now available, effective treatment options are still needed. A highly interesting target for treatment is the replication process of the virus, in which the viral polymerase complex is critical. A critical protein of this complex is the RSV large (L) protein, which harbors multiple enzymatic functions that are all interesting targets for antiviral drug discovery. Unfortunately, not all structural parts of this L protein are currently resolved, which makes antiviral drug design and optimization challenging. In this review, an overview is given of current knowledge on the RSV L structure. Furthermore, a comparison is made between the L proteins of RSV and human metapneumovirus (hMPV), which, based on their sequence similarity, could shed light on missing structural gaps. New insights into the RSV and hMPV L protein structures are given, by modeling unresolved domains with AlphaFold2 and Alphafold3. While more structural studies are needed to confirm the modeling data, there is clearly potential for development of treatments targeting the L protein, for RSV and closely related viruses.