蛋白质聚集与许多人类疾病相关。蛋白质聚集体的结构和形状不同。迄今为止，开发有效的聚集抑制剂并应用于临床的策略尚未成功。在这里，我们开发了一系列肽，针对序列和结构无关的无定形和纤维状蛋白质聚集体的早期聚集阶段。在机械分化发生之前，它们对动态前体起作用。使用肽阵列，我们首先鉴定了抑制 Axin 肿瘤抑制因子的熔融球状、易聚集突变体的无定形聚集的肽。优化表明，肽的活性并不取决于其序列，而是取决于其分子决定因素：20-30% 的柔性残基、30-40% 的脂肪族残基和 20-30% 的芳香族残基组成，疏水性/亲水性比率接近 1，以及不同性质的残基在整个序列中的均匀分布。这些肽还抑制了 Tau（一种在阿尔茨海默病中形成淀粉样蛋白的无序蛋白）的纤维颤动，并减缓了亨廷顿外显子 1（亨廷顿病中的一种淀粉样蛋白生成蛋白）的纤维颤动，两者都与 Axin 完全无关。因此，我们的化合物针对不同聚集机制的早期聚集阶段，抑制无定形和淀粉样蛋白聚集。这种跨机制、多靶点的聚集抑制剂可能是开发针对各种蛋白质聚集疾病的候选药物的先导化合物。© 2024 Wiley‐VCH GmbH。

Protein aggregation correlates with many human diseases. Protein aggregates differ in structure and shape. Strategies to develop effective aggregation inhibitors that reach the clinic failed so far. Here, we developed a family of peptides targeting early aggregation stages for both amorphous and fibrillar aggregates of proteins unrelated in sequence and structure. They act on dynamic precursors before mechanistic differentiation takes place. Using peptide arrays, we first identified peptides inhibiting the amorphous aggregation of a molten globular, aggregation-prone mutant of the Axin tumor suppressor. Optimization revealed that the peptides activity did not depend on their sequences but rather on their molecular determinants: a composition of 20-30% flexible, 30-40% aliphatic and 20-30% aromatic residues, a hydrophobicity/hydrophilicity ratio close to 1, and an even distribution of residues of different nature throughout the sequence. The peptides also suppressed fibrillation of Tau, a disordered protein that forms amyloids in Alzheimer's disease, and slowed down that of Huntingtin Exon1, an amyloidogenic protein in Huntington's disease, both entirely unrelated to Axin. Our compounds thus target early aggregation stages of different aggregation mechanisms, inhibiting both amorphous and amyloid aggregation. Such cross-mechanistic, multi-targeting aggregation inhibitors may be lead compounds for developing drug candidates against various protein aggregation diseases.© 2024 Wiley‐VCH GmbH.