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 ~10³ 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 × 10⁶ 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.

SARS-CoV-2 (SARS2) 的爆发已导致全球 COVID-19 大流行。SARS2 的刺突蛋白 (SARS2-S) 识别宿主受体，包括 ACE2，从而在复杂的生物力学环境中启动病毒进入。在这里，我们揭示了由宿主细胞膜弯曲产生的张力，增强了 ACE2 的尖峰识别，并加速了尖峰 S1 亚基与 S2 亚基的分离，以快速启动病毒融合机制。从机制上讲，这种机械激活是通过力诱导刺突受体结合域的打开和旋转来实现的，以延长刺突/ACE2结合的键寿命，在 10 pN 力下比 SARS-S 与 ACE2 结合的键寿命长 4 倍应用，然后通过力加速 S1/S2 分离，高达 ~10 ³比无力条件下的速度快几倍。有趣的是，SARS2-S D614G 突变体是一种更具传染性的变体，它显示出更强的 3 倍力依赖性 ACE2 结合和 35 倍更快的力诱导 S1/S2 脱离。我们还发现，来自恢复期 COVID-19 患者的具有强中和能力的抗 S1/S2 非 RBD 阻断抗体可以在力作用下将 S1/S2 脱离减少 3 × 10 ⁶倍。我们的研究阐明了尖峰激活的机械化学和开发一种非 RBD 阻断但 S1/S2 锁定的治疗策略，以防止 SARS2 入侵。