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SARS-CoV-2 spike host cell surface exposure promoted by a COPI sorting inhibitor
Acta Pharmaceutica Sinica B ; (6): 3043-3053, 2023.
Article in En | WPRIM | ID: wpr-982851
Responsible library: WPRO
ABSTRACT
Via an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-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 (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. 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-CoV-2 evolution mechanism driven by S folding and trafficking mutations.
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Full text: 1 Index: WPRIM Language: En Journal: Acta Pharmaceutica Sinica B Year: 2023 Type: Article
Full text: 1 Index: WPRIM Language: En Journal: Acta Pharmaceutica Sinica B Year: 2023 Type: Article