Michael Acceptor-Based Peptidomimetic Inhibitor of Main Protease from Porcine Epidemic Diarrhea Virus

Porcine epidemic diarrhea virus (PEDV) causes high mortality in pigs. PEDV main protease (M<sup>pro</sup>) plays an essential role in viral replication. We solved the structure of PEDV M<sup>pro</sup> complexed with peptidomimetic inhibitor N3 carrying a Michael acceptor warhead, revealing atomic level interactions. We further designed a series of 17 inhibitors with altered side groups. Inhibitors M2 and M17 demonstrated enhanced specificity against PEDV M<sup>pro</sup>. These compounds have potential as future therapeutics to combat PEDV infection.