SARS-CoV-2utilizes its spike protein to recognize host angiotensin-converting enzyme II(ACE2) receptor, which induces subsequent S1/S2 detachment of spike for formingfusion machinery to invade host cells. However, only small structural changesof spike occur upon ACE2 binding, which raises questions whether these smallconformational changes are enough to trigger the detachment of tightlyassociated S1/S2 subunits and, if not, whether additional factors are required.
The research team led byDr. CHEN Wei from the Zhejiang UniversitySchool of Medicine published an article entitled “Mechanicalactivation of spike fosters SARS-CoV-2 viral infection” online on August31 in Cell Research. This research demonstrates that the mechanicalforce can enhance spike/ACE2 interaction and accelerate the S1/S2 detachment,thus facilitating viral invasion.
Fig.1. 《Cell Research》2020.10 CoverImage. A SARS-CoV-2 virion (monster egg, inside of which is amonster representing viral RNA) touches host-cell plasma membrane (blue bendingground) producing tensile force (children’s pulling), which not onlystrengthens spike–ACE2 (children) recognition, but also accelerates the S1/S2separation to boost viral fusion machinery.
Once a virion attaches tothe host cells, the pulling force on the spike/ACE2 bonds at the contact zoneedge is the roughly ranging from 0 to 30 pN range according to the theoretical analysisof this research. This pulling force would enhance the invasion of SARS-CoV-2into host cells by mechanically strengthening its spike binding with host ACE2receptors and by accelerating S1/S2 detachment to destabilize the pre-fusionspike trimer. Unexpectedly, this research finds that D614G mutation in spike(shared by Alpha, Beta, Delta, Gamma and Lambda strains) shows 3-time strongerforce-dependent ACE2 binding and 35-time faster force-induced S1/S2 detachment,which provides a novel molecular mechanism to explain the high infectivity of D614G-relatedstrains.
In addition, this studyalso identifies an anti-S1/S2 non-RBD-blocking antibody that is derived fromconvalescent COVID-19 patients and with potent neutralizing activity for virusinfection can impede S1/S2 detachment by 3×106 times under force. Basedon these findings, this study proposes an alternative non-RBD-blocking butS1/S2-binding neutralizing strategy: exploiting S1/S2-targeting mAbs tostabilize SARS2-S structure by locking SARS2-S conformation to prevent S1/S2detachment and follow-up S2 fusion machinery formation. S1/S2-lockingneutralizing strategy potentially can compensate or complimentreceptor-blocking strategy no matter what other novel spike’s receptor arefound.
Figure2. The model for mechano-activation ofSARS-CoV-2 spike and its inhibition by non-RBD-blocking, S1/S2-targeting, butneutralizing antibody
“Our study sheds light onmechano-chemistry of spike activation and on developing a non-RBD-blocking butS1/S2-locking therapeutic strategy to prevent viral invasion,” said CHEN Wei. “Thisstudy is a successful case of interdisciplinary cooperation, and also a major breakthroughin the fields of biomechanics and mechanobiology, single molecule biophysicsand virology.”
