Understanding the mechanism of action of compounds capable of inhibiting amyloid-fibril formation is critical to the development of potential therapeutics against protein-misfolding diseases. A fundamental challenge for progress is the range of possible target species and the disparate timescales involved, since the aggregating proteins are simultaneously the reactants, products, intermediates, and catalysts of the reaction. It is a complex problem, therefore, to choose the states of the aggregating proteins that should be bound by the compounds to achieve the most potent inhibition. We present here a comprehensive kinetic theory of amyloid-aggregation inhibition that reveals the fundamental thermodynamic and kinetic signatures characterizing effective inhibitors by identifying quantitative relationships between the aggregation and binding rate constants. These results provide general physical laws to guide the design and optimization of inhibitors of amyloid-fibril formation, revealing in particular the important role of on-rates in the binding of the inhibitors.

理解能够抑制淀粉样蛋白原纤维形成的化合物的作用机理对于开发针对蛋白质错误折叠疾病的潜在疗法至关重要。进展的基本挑战是可能的目标物种的范围和涉及的不同时间尺度，因为聚集的蛋白质同时是反应的反应物，产物，中间体和催化剂。因此，选择化合物应结合的聚集蛋白的状态以实现最有效的抑制是一个复杂的问题。我们在这里介绍了淀粉样蛋白聚集抑制的综合动力学理论，该理论揭示了通过鉴定聚集和结合速率常数之间的定量关系来表征有效抑制剂的基本热力学和动力学特征。这些结果提供了一般的物理规律，以指导淀粉样蛋白原纤维形成抑制剂的设计和优化，特别揭示了速率对抑制剂结合的重要作用。