Omicron Spike Protein is Vulnerable to Reduction

SARS-CoV-2 virus spike (S) protein is an envelope protein responsible for binding to the ACE2 receptor, driving subsequent entry into host cells. The existence of multiple disulfide bonds in the S protein makes it potentially susceptible to reductive cleavage. Using a tri-part split luciferase-based binding assay, we evaluated the impacts of chemical reduction on S proteins from different virus variants and found that those from the Omicron family are highly vulnerable to reduction. Through manipulation of different Omi-cron mutations, we found that alterations in the receptor binding module (RBM) are the major determi-nants of this vulnerability. Specifically we discovered that Omicron mutations facilitate the cleavage of C480-C488 and C379-C432 disulfides, which consequently impairs binding activity and protein stability. The vulnerability of Omicron S proteins suggests a mechanism that can be harnessed to treat specific SARS-CoV-2 strains.(c) 2023 Published by Elsevier Ltd.

Automated summary

The spike (S) protein of the SARS-CoV-2 virus is responsible for binding to the ACE2 receptor and entering host cells. Reductive cleavage may occur due to the presence of multiple disulfide bonds in the S protein. In this study, the vulnerability of S proteins from different virus variants, especially the Omicron family, to reduction was evaluated using a luciferase-based binding assay. It was found that Omicron mutations in the receptor binding module (RBM) facilitate cleavage of certain disulfide bonds, impairing binding activity and protein stability. The vulnerability of Omicron S proteins suggests a potential mechanism for treating specific SARS-CoV-2 strains.