Garfagnini Tommaso, Hayouka Zvi, Friedler Assaf
Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram Jerusalem 9190401 Israel
Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, The Robert H. Smith Faculty of Agriculture, Food and Environment Rehovot 76100 Israel
RSC Chem Biol. 2025 Jul 10. doi: 10.1039/d5cb00141b.
Aggregation of dysfunctional proteins can lead to a variety of diseases including cancer. We have previously developed chaperone-derived peptides that inhibit aggregation of the cancer-related L106R mutant of Axin RGS. Here we show that significantly improved inhibition was achieved using random peptide mixtures (RPMs) designed to mimic the chemical characteristics of the chaperone-like peptides. 20-mer RPMs of tryptophan and lysine suppressed aggregation of Axin RGS L106R with up to 50-fold improved activity compared to parent inhibitors. Conversely, peptides derived from the lead hotspot of Axin RGS aggregation that were designed to be specific, were unable to prevent aggregation of the protein. RPMs constitute the most efficient strategy to date to magnify peptide inhibitory activity against Axin RGS L106R aggregation, as they contain multiple active species and conformations that cover a larger inhibitory space and shield multiple hotspots at once. Our results demonstrate that the chemical composition of the peptide, and not the specific sequence, is the key factor for inhibitory activity.
功能失调蛋白质的聚集会导致包括癌症在内的多种疾病。我们之前开发了伴侣蛋白衍生肽，其可抑制与癌症相关的Axin RGS的L106R突变体的聚集。在此我们表明，使用旨在模拟伴侣蛋白样肽化学特性的随机肽混合物（RPM）可实现显著增强的抑制作用。色氨酸和赖氨酸组成的20聚体RPM抑制Axin RGS L106R的聚集，与亲本抑制剂相比活性提高了50倍。相反，源自Axin RGS聚集的主要热点区域且设计为具有特异性的肽无法阻止该蛋白的聚集。RPM是迄今为止放大肽对Axin RGS L106R聚集抑制活性的最有效策略，因为它们包含多个活性物种和构象，可覆盖更大的抑制空间并同时屏蔽多个热点。我们的结果表明，肽的化学组成而非特定序列是抑制活性的关键因素。
