Mechanical activation of spike fosters SARS-CoV-2 viral infection

• Published in: Cell research Vol. 31; no. 10; pp. 1047 - 1060
• Main Authors: Hu, Wei, Zhang, Yong, Fei, Panyu, Zhang, Tongtong, Yao, Danmei, Gao, Yufei, Liu, Jia, Chen, Hui, Lu, Qiao, Mudianto, Tenny, Zhang, Xinrui, Xiao, Chuxuan, Ye, Yang, Sun, Qiming, Zhang, Jing, Xie, Qi, Wang, Pei-Hui, Wang, Jun, Li, Zhenhai, Lou, Jizhong, Chen, Wei
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.10.2021; Nature Publishing Group
• Subjects: 631/337; 631/535; ACE2; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - metabolism; Antibodies; Antibodies, Neutralizing - immunology; Binding; Binding Sites; Biomechanics; Biomedical and Life Sciences; Blocking antibodies; Cell Biology; Cell membranes; Coronaviruses; COVID-19; COVID-19 - diagnosis; COVID-19 - therapy; COVID-19 - virology; COVID-19 Serotherapy; Humans; Hydrogen-Ion Concentration; Immunization, Passive; Life Sciences; Locking; Molecular Dynamics Simulation; Pandemics; Protein Binding; Protein Domains - immunology; Protein Subunits - chemistry; Protein Subunits - immunology; Protein Subunits - metabolism; Receptors; SARS-CoV-2 - isolation & purification; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - immunology; Spike Glycoprotein, Coronavirus - metabolism; Spike protein; Tensile Strength; Viral diseases; Viral infections; Virus Internalization
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/s41422-021-00558-x

The outbreak of SARS-CoV-2 (SARS2) has caused a global COVID-19 pandemic. The spike protein of SARS2 (SARS2-S) recognizes host receptors, including ACE2, to initiate viral entry in a complex biomechanical environment. Here, we reveal that tensile force, generated by bending of the host cell membrane, strengthens spike recognition of ACE2 and accelerates the detachment of spike’s S1 subunit from the S2 subunit to rapidly prime the viral fusion machinery. Mechanistically, such mechano-activation is fulfilled by force-induced opening and rotation of spike’s receptor-binding domain to prolong the bond lifetime of spike/ACE2 binding, up to 4 times longer than that of SARS-S binding with ACE2 under 10 pN force application, and subsequently by force-accelerated S1/S2 detachment which is up to ~10 3 times faster than that in the no-force condition. Interestingly, the SARS2-S D614G mutant, a more infectious variant, shows 3-time stronger force-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment. We also reveal that an anti-S1/S2 non-RBD-blocking antibody that was derived from convalescent COVID-19 patients with potent neutralizing capability can reduce S1/S2 detachment by 3 × 10 6 times under force. Our study sheds light on the mechano-chemistry of spike activation and on developing a non-RBD-blocking but S1/S2-locking therapeutic strategy to prevent SARS2 invasion.