Large protein (L) of respiratory syncytial virus (L protein)

The L protein of respiratory syncytial virus (RSV) is a ~250 kDa multifunctional enzyme that serves as the viral RNA-dependent RNA polymerase, essential for replicating the viral genome and transcribing viral mRNAs[1][3]. It possesses three conserved enzymatic domains: an RNA-dependent RNA polymerase (RdRp) for RNA synthesis, a polyribonucleotidyl transferase (PRNTase/capping domain) for mRNA 5’ capping, and a methyltransferase (MTase) domain for cap methylation[1]. The C-terminal domain is variable across nonsegmented negative-sense (NNS) RNA viruses. The L protein is always complexed with the viral phosphoprotein (P), which connects it to the viral nucleocapsid, and the M2-1 protein is also required for efficient transcription[1][5]. Recent cryo-EM structures reveal a striking "tentacular" arrangement of P around L, with each P monomer adopting a distinct conformation, highlighting structural plasticity and providing a framework for inhibitor design[1][2][4]. The L protein is a major target for antiviral drug development due to its central role in the viral life cycle[2][3]. Inhibitors targeting L have demonstrated antiviral activity against both RSV A and B subtypes, and resistance mutations have been mapped to the capping domain, confirming L as the direct target[3]. The complex interplay between L, P, and M2-1 makes the polymerase complex an attractive but challenging target for therapeutic intervention.

Other names

RNA-dependent RNA polymerase (RdRp)viral polymeraseRSV polymerase

Inhibition of viral RNA-dependent RNA polymerase activity, blocking RNA synthesis and capping, direct binding to L protein domains (e.g., capping domain, polymerase domain), competitive or allosteric inhibition