Coronaviruses (CoVs) can cause highly prevalent diseases in humans and animals. 
Feline infectious peritonitis virus (FIPV) belongs to the genus 
Alphacoronavirus, resulting in a lethal systemic granulomatous disease called 
feline infectious peritonitis (FIP), which is one of the most important fatal 
infectious diseases of cats worldwide. No specific vaccines or drugs have been 
approved to treat FIP. CoV main proteases (M(pro)s) play a pivotal role in viral 
transcription and replication, making them an ideal target for drug development. 
Here, we report the crystal structure of FIPV M(pro) in complex with dual 
inhibitors, a zinc ion and a Michael acceptor. The complex structure elaborates 
a unique mechanism of two distinct inhibitors synergizing to inactivate the 
protease, providing a structural basis to design novel antivirals and suggesting 
the potential to take advantage of zinc as an adjunct therapy against 
CoV-associated diseases.
IMPORTANCE: Coronaviruses (CoVs) have the largest genome size among all RNA 
viruses. CoV infection causes various diseases in humans and animals, including 
severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome 
(MERS). No approved specific drugs or vaccinations are available to treat their 
infections. Here, we report a novel dual inhibition mechanism targeting CoV main 
protease (M(pro)) from feline infectious peritonitis virus (FIPV), which leads 
to lethal systemic granulomatous disease in cats. M(pro), conserved across all 
CoV genomes, is essential for viral replication and transcription. We 
demonstrated that zinc ion and a Michael acceptor-based peptidomimetic inhibitor 
synergistically inactivate FIPV M(pro). We also solved the structure of FIPV 
M(pro) complexed with two inhibitors, delineating the structural view of a dual 
inhibition mechanism. Our study provides new insight into the pharmaceutical 
strategy against CoV M(pro) through using zinc as an adjuvant therapy to enhance 
the efficacy of an irreversible peptidomimetic inhibitor.