Protein misfolding and aggregation are common pathological features of several human diseases, including Alzheimer’s disease and type 2 diabetes. Here, we report an integrated and generalizable bacterial system for the facile discovery of chemical rescuers of disease-associated protein misfolding. In this system, large combinatorial libraries of macrocyclic molecules are biosynthesized in Escherichia coli cells and simultaneously screened for their ability to rescue pathogenic protein misfolding and aggregation using a flow cytometric assay. We demonstrate the effectiveness of this approach by identifying drug-like, head-to-tail cyclic peptides that modulate the aggregation of the Alzheimer’s disease-associated amyloid β peptide. Biochemical, biophysical and biological assays using isolated amyloid β peptide, primary neurons and various established Alzheimer’s disease nematode models showed that the selected macrocycles potently inhibit the formation of neurotoxic amyloid β peptide aggregates. We also applied the system to the identification of misfolding rescuers of mutant Cu/Zn superoxide dismutase—an enzyme linked with inherited forms of amyotrophic lateral sclerosis. Overall, the system enables the identification of molecules with therapeutic potential for rescuing the misfolding of disease-associated polypeptides.

蛋白质错误折叠和聚集是几种人类疾病（包括阿尔茨海默氏病和2型糖尿病）的常见病理特征。在这里，我们报告了一个易于发现与疾病相关的蛋白质错误折叠的化学拯救者的综合的和可概括的细菌系统。在这个系统中，大环分子的大型组合文库是在大肠杆菌中生物合成的细胞，同时使用流式细胞仪检测其拯救病原蛋白错误折叠和聚集的能力。我们通过鉴定可调节阿尔茨海默氏病相关淀粉样β肽聚集的类药物，从头到尾的环状肽，证明了该方法的有效性。使用分离的淀粉样蛋白β肽，原代神经元和各种已建立的阿尔茨海默氏病线虫模型的生化，生物物理和生物学分析表明，所选大环化合物有效抑制了神经毒性淀粉样蛋白β肽聚集体的形成。我们还将该系统应用于识别突变型Cu / Zn超氧化物歧化酶的错折叠拯救基因，该酶与遗传形式的肌萎缩性侧索硬化症有关。全面的，