Susceptibility of paramyxoviruses and filoviruses to inhibition by 2′-monofluoro- and 2′-difluoro-4′-azidocytidine analogs

Ebolaviruses, marburgviruses, and henipaviruses are zoonotic pathogens belonging to the Filoviridae and Paramyxoviridae families. They exemplify viruses that continue to spill over into the human population, causing outbreaks characterized by high mortality and significant clinical sequelae in survivors of infection. There are currently no approved small molecule therapeutics for use in humans against these viruses. In this study, we evaluated the antiviral activity of the nucleoside analog 4′-azidocytidine (4′N(3)-C, R1479) and its 2′-monofluoro- and 2′-difluoro-modified analogs (2′F-4′N(3)-C and 2′diF-4′N(3)-C) against representative paramyxoviruses (Nipah virus, Hendra virus, measles virus, and human parainfluenza virus 3) and filoviruses (Ebola virus, Sudan virus, and Ravn virus). We observed enhanced antiviral activity against paramyxoviruses with both 2′diF-4′N(3)-C and 2′F-4′N(3)-C compared to R1479. On the other hand, while R1479 and 2′diF-4′N(3)-C inhibited filoviruses similarly to paramyxoviruses, we observed 10-fold lower filovirus inhibition by 2′F-4′N(3)-C. To our knowledge, this is the first study to compare the susceptibility of paramyxoviruses and filoviruses to R1479 and its 2′-fluoro-modified analogs. The activity of these compounds against negative-strand RNA viruses endorses the development of 4′-modified nucleoside analogs as broad-spectrum therapeutics against zoonotic viruses of public health importance.