Discovery of Potent and Broad-Spectrum Pyrazolopyridine-Containing Antivirals against Enteroviruses D68, A71, and Coxsackievirus B3 by Targeting the Viral 2C Protein

The enterovirus genus
of the picornavirus family
contains many important human pathogens. EV-D68 primarily infects
children, and the disease manifestations range from respiratory illnesses
to neurological complications such as acute flaccid myelitis (AFM).
EV-A71 is a major pathogen for the hand, foot, and mouth disease (HFMD)
in children and can also lead to AFM and death in severe cases. CVB3
infection can cause cardiac arrhythmias, acute heart failure, as well
as type 1 diabetes. There is currently no FDA-approved antiviral for
any of these enteroviruses. In this study, we report our discovery
and development of pyrazolopyridine-containing small molecules with
potent and broad-spectrum antiviral activity against multiple strains
of EV-D68, EV-A71, and CVB3. Serial viral passage experiments, coupled
with reverse genetics and thermal shift binding assays, suggested
that these molecules target the viral protein 2C. Overall, the pyrazolopyridine
inhibitors represent a promising class of candidates for the urgently
needed nonpolio enterovirus antivirals.