SARS-CoV-2 spike host cell surface exposure promoted by a COPI sorting inhibitor  

作　　者：Yiqun Li Mingrui Yang Yanan Nan Jiaming Wang Sanjiao Wang Dongxiao Cui Jiajian Guo Pengfei He Wenxin Dai Shuqi Zhou Yue Zhang Wenfu Ma 

机构地区：[1]School of Life Science,Beijing University of Chinese Medicine,Beijing 102488,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期3043-3053,共11页药学学报（英文版）

基　　金：supported by Startup fund program at Beijing University of Chinese Medicine(BUCM)(90011451310011,China)to Wenfu Ma;the emergency fund against COVID-19 program at BUCM(1000061223476,China)to Wenfu Ma;the innovation team and talents cultivation program of national administration of traditional Chinese medicine(ZYYCXTD-C202006,China)to Wenfu Ma。

摘　　要：Via an insufficient coat protein complex I(COPI)retrieval signal,the majority of SARSCo V-2 spike(S)is resident in host early secretory organelles and a tiny amount is leaked out in cell surface.Only surface-exposed S can be recognized by B cell receptor(BCR)or anti-S therapeutic monoclonal antibodies(m Abs)that is the trigger step for B cell activation after S m RNA vaccination or infected cell clearance by S m Abs.Now,a drug strategy to promote S host surface exposure is absent.Here,we first combined structural and biochemical analysis to characterize S COPI sorting signals.A potent S COPI sorting inhibitor was then invented,evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity(ADCC).Importantly,with the inhibitor as a probe,we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations,possibly corresponding to its ER chaperone association.Our findings not only suggest COPI is a druggable target against COVID-19,but also highlight SARS-Co V-2 evolution mechanism driven by S folding and trafficking mutations.

关 键 词：COPI inhibitor SARS-CoV-2 spike Spike sorting motifs Protein folding Protein trafficking Anti-COVID-19 Omicron variants and drug discovery 

分 类 号：R96[医药卫生—药理学]