Small Molecule Inhibition of Mononegavirales RNA Polymerases

The order Mononegavirales includes several non-segmented negative-sense RNA viruses that are significant human pathogens, whose transcription and replication depend on multifunctional RNA-dependent RNA polymerase (L protein). Recent discoveries in cryo-electron microscopy (cryo-EM) have elucidated the structures of these polymerases and their interactions with small-molecule inhibitors, providing possible insights for antiviral design. This review summarizes current developments and discoveries in small-molecule inhibition of Mononegavirales polymerases, exploring nucleoside/nucleotide inhibitors that target the catalytic site and non-nucleoside inhibitors that engage allosteric pockets within the L protein. By combining biochemical and structural findings, these studies reveal conserved druggable pockets, providing opportunities for the development of broad-spectrum antivirals drugs against Mononegavirales pathogens.