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Additionally, leveraging the established role of COPI-mediated trafficking in S localization, a compound is developed to disrupt S-COPI binding, promoting S secretion to the cell surface and effectively reducing viral titers. Our findings revealed a critical host\u2013pathogen interaction that drives S incorporation into virions and identified ERM proteins as key facilitators of coronavirus assembly. Furthermore, our study suggests an antiviral strategy by targeting the S-COPI trafficking pathway. 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