In:
MedComm, Wiley, Vol. 5, No. 6 ( 2024-06)
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‐CF 3 , 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‐CF 3 as host factor coatomer subunit zeta‐1 (COPZ1). Mechanistically, MPA‐CF 3 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‐CF 3 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‐CF 3 against EV‐A71 may offer an alternative COPZ1‐involved therapeutic pathway for enterovirus infection.
Type of Medium:
Online Resource
ISSN:
2688-2663
,
2688-2663
Language:
English
Publisher:
Wiley
Publication Date:
2024
detail.hit.zdb_id:
3021470-1