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 (Mpro) plays an essential role
in viral replication. We solved the structure of PEDV Mpro 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 Mpro. These compounds have potential as future therapeutics to combat
PEDV infection.

猪流行性腹泻病毒（Porcine epidemic diarrhea virus, PEDV）可导致猪只出现高致死率。该病毒的主蛋白酶（main protease, Mpro）在病毒复制过程中发挥关键作用。本研究解析了携带迈克尔受体弹头（Michael acceptor warhead）的拟肽抑制剂N3（peptidomimetic inhibitor N3）与PEDV主蛋白酶的复合物结构，揭示了二者在原子层面的相互作用机制。研究团队进一步设计了17种侧链基团经过修饰的抑制剂，其中抑制剂M2与M17对PEDV主蛋白酶展现出更优异的特异性。这类化合物有望成为未来对抗猪流行性腹泻病毒感染的潜在治疗候选药物。