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Publication Abstract from PubMed

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.

SARS-CoV-2 spike host cell surface exposure promoted by a COPI sorting inhibitor.,Li Y, Yang M, Nan Y, Wang J, Wang S, Cui D, Guo J, He P, Dai W, Zhou S, Zhang Y, Ma W Acta Pharm Sin B. 2023 Apr 18;13(7):3043-53. doi: 10.1016/j.apsb.2023.04.007. PMID:37360012^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.