Maleimide–thiol reactions are widely used to produce protein–polymer conjugates for therapeutics. However, maleimide–thiol adducts are unstable in vivo or in the presence of thiol-containing compounds because of the elimination of the thiosuccinimide linkage through a retro-Michael reaction or thiol exchange. Here, using single-molecule force spectroscopy, we show that applying an appropriate stretching force to the thiosuccinimide linkage can considerably stabilize the maleimide–thiol adducts, in effect using conventional mechanochemistry of force-accelerated bond dissociation to unconventionally stabilize an adjacent bond. Single-molecule kinetic analysis and bulk structural characterizations suggest that hydrolysis of the succinimide ring is dominant over the retro-Michael reaction through a force-dependent kinetic control mechanism, and this leads to a product that is resistant to elimination. This unconventional mechanochemical approach enabled us to produce stable polymer–protein conjugates by simply applying a mechanical force to the maleimide–thiol adducts through mild ultrasonication. Our results demonstrate the great potential of mechanical force for stimulating important productive chemical transformations.

马来酰亚胺-硫醇反应广泛用于生产用于治疗的蛋白质-聚合物偶联物。然而，马来酰亚胺-硫醇加合物在体内或在含硫醇化合物存在下不稳定，因为通过逆迈克尔反应或硫醇交换消除了硫代琥珀酰亚胺键。在这里，使用单分子力谱，我们表明对硫代琥珀酰亚胺键施加适当的拉伸力可以显着稳定马来酰亚胺-硫醇加合物，实际上是使用力加速键解离的常规机械化学来非常规地稳定相邻键。单分子动力学分析和整体结构表征表明，通过力依赖性动力学控制机制，琥珀酰亚胺环的水解在逆迈克尔反应中占主导地位，这导致了一种抗消除的产品。这种非常规的机械化学方法使我们能够通过温和的超声处理对马来酰亚胺-硫醇加合物简单地施加机械力来生产稳定的聚合物-蛋白质缀合物。我们的结果证明了机械力在刺激重要的生产性化学转化方面的巨大潜力。