Chemoproteomics enables identification of coatomer subunit zeta‐1 targeted by a small molecule for enterovirus A71 inhibition
Xiaoyong Li,
Jin Zhang,
Yaxin Xiao,
Hao Song,
Yuexiang Li,
Wei Li,
Ruiyuan Cao,
Song Li,
Yong Qin,
Chu Wang,
Wu Zhong
Affiliations
Xiaoyong Li
Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant‐Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University Chengdu China
Jin Zhang
College of Chemistry and Molecular Engineering Peking University Beijing China
Yaxin Xiao
Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant‐Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University Chengdu China
Hao Song
Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant‐Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University Chengdu China
Yuexiang Li
National Engineering Research Center for the Emergence Drugs Beijing Institute of Pharmacology and Toxicology Beijing China
Wei Li
National Engineering Research Center for the Emergence Drugs Beijing Institute of Pharmacology and Toxicology Beijing China
Ruiyuan Cao
National Engineering Research Center for the Emergence Drugs Beijing Institute of Pharmacology and Toxicology Beijing China
Song Li
National Engineering Research Center for the Emergence Drugs Beijing Institute of Pharmacology and Toxicology Beijing China
Yong Qin
Key Laboratory of Drug‐Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant‐Sourced Drug, and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy Sichuan University Chengdu China
Chu Wang
College of Chemistry and Molecular Engineering Peking University Beijing China
Wu Zhong
National Engineering Research Center for the Emergence Drugs Beijing Institute of Pharmacology and Toxicology Beijing China
Abstract Human enterovirus A71 (EV‐A71) is a significant etiological agent responsible for epidemics of hand, foot, and mouth disease (HFMD) in Asia‐Pacific regions. There are presently no licensed antivirals against EV‐A71, and the druggable target for EV‐A71 remains very limited. The phenotypic hit 10,10′‐bis(trifluoromethyl) marinopyrrole A derivative, herein termed MPA‐CF3, is a novel potent small‐molecule inhibitor against EV‐A71, but its pharmacological target(s) and antiviral mechanisms are not defined. Here, quantitative chemoproteomics deciphered the antiviral target of MAP‐CF3 as host factor coatomer subunit zeta‐1 (COPZ1). Mechanistically, MPA‐CF3 disrupts the interaction of COPZ1 with the EV‐A71 nonstructural protein 2C by destabilizing COPZ1 upon binding. The destruction of this interaction blocks the coatomer‐mediated transport of 2C to endoplasmic reticulum, and ultimately inhibits EV‐A71 replication. Taken together, our study disclosed that MPA‐CF3 can be a structurally novel host‐targeting anti‐EV‐A71 agent, providing a structural basis for developing the COPZ1‐targeting broad‐spectrum antivirals against enteroviruses. The mechanistic elucidation of MPA‐CF3 against EV‐A71 may offer an alternative COPZ1‐involved therapeutic pathway for enterovirus infection.
