Like SARS-CoV-2, one of the most deadly organisms in the Americas with case fatality rates of up to roughly 40% and human-to-human transmission with documented super-spreader events is another airborne respiratory virus known as Andes virus (ANDV; family Hantaviridae). We have solved the tridimensional structure and biochemically characterized a metal-dependent endoribonuclease domain (illustrated in the figure on the right) at the N-terminal site of the virus L protein. This enzyme is responsible for initiating the virus's genome transcription via a cap-snatching mechanism, making it a driving factor in determining the magnitude of viral amplification and, therefore, the progression of the infectious disease. Its vital role in the early stages of the virus lifecycle and uniqueness to segmented single-stranded RNA viruses defines it as a strategic pharmacological target.
Proof-of-concept for the clinical applicability of cap-snatching endonuclease (Cap-ENDO) inhibitors is the recently approved antiviral Xofluza. Baloxavir acid, the active compound in Xofluza, targets the endonuclease of the Influenza virus. The drug, administered as a single-dose regimen, has proven effective against circulating strains resistant to current treatments.