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The phenotypic hit 10,10\u2032\u2010bis(trifluoromethyl) marinopyrrole A derivative, herein termed MPA\u2010CF<jats:sub>3<\/jats:sub>, is a novel potent small\u2010molecule inhibitor against EV\u2010A71, but its pharmacological target(s) and antiviral mechanisms are not defined. Here, quantitative chemoproteomics deciphered the antiviral target of MAP\u2010CF<jats:sub>3<\/jats:sub> as host factor coatomer subunit zeta\u20101 (COPZ1). Mechanistically, MPA\u2010CF<jats:sub>3<\/jats:sub> disrupts the interaction of COPZ1 with the EV\u2010A71 nonstructural protein 2C by destabilizing COPZ1 upon binding. The destruction of this interaction blocks the coatomer\u2010mediated transport of 2C to endoplasmic reticulum, and ultimately inhibits EV\u2010A71 replication. Taken together, our study disclosed that MPA\u2010CF<jats:sub>3<\/jats:sub> can be a structurally novel host\u2010targeting anti\u2010EV\u2010A71 agent, providing a structural basis for developing the COPZ1\u2010targeting broad\u2010spectrum antivirals against enteroviruses. The mechanistic elucidation of MPA\u2010CF<jats:sub>3<\/jats:sub> against EV\u2010A71 may offer an alternative COPZ1\u2010involved therapeutic pathway for enterovirus infection.<\/jats:p>","DOI":"10.1002\/mco2.587","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T11:02:59Z","timestamp":1717585379000},"source":"Crossref","is-referenced-by-count":6,"title":["Chemoproteomics enables identification of coatomer subunit zeta\u20101 targeted by a small molecule for enterovirus A71 inhibition"],"prefix":"10.1002","volume":"5","author":[{"given":"Xiaoyong","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Drug\u2010Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant\u2010Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University  Chengdu China"},{"name":"National Engineering Research Center for the Emergence 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