The Institute of Chemistry, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem, Israel.
Department of Microbiology and Molecular Genetics, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Chemistry. 2020 Aug 12;26(45):10240-10249. doi: 10.1002/chem.202000465. Epub 2020 Jul 7.
Intrinsically disordered regions in proteins (IDRs) mediate many disease-related protein-protein interactions. However, the unfolded character and continuous conformational changes of IDRs make them difficult to target for therapeutic purposes. Here, we show that a designed peptide based on the disordered p53 linker domain can be used to target a partner IDR from the anti-apoptotic iASPP protein, promoting apoptosis of cancer cells. The p53 linker forms a hairpin-like structure with its two termini in close proximity. We designed a peptide derived from the disordered termini without the hairpin, designated as p53 LinkTer. The LinkTer peptide binds the disordered RT loop of iASPP with the same affinity as the parent p53 linker peptide, and inhibits the p53-iASPP interaction in vitro. The LinkTer peptide shows increased stability to proteolysis, penetrates cancer cells, causes nuclei shrinkage, and compromises the viability of cells. We conclude that a designed peptide comprising only the IDR from a peptide sequence can serve as an improved inhibitor since it binds its target protein without the need for pre-folding, paving the way for therapeutic targeting of IDRs.
蛋白质中的无规则区域（IDR）介导许多与疾病相关的蛋白-蛋白相互作用。然而，IDR 的无规则特性和连续的构象变化使其难以成为治疗靶点。在这里，我们展示了一种基于无序 p53 连接域的设计肽可用于靶向抗凋亡 iASPP 蛋白的伴侣 IDR，从而促进癌细胞凋亡。p53 连接子形成发夹样结构，其两个末端非常接近。我们设计了一种源自无序末端的肽，没有发夹，命名为 p53 LinkTer。LinkTer 肽与亲本 p53 连接肽以相同的亲和力结合 iASPP 的无序 RT 环，并在体外抑制 p53-iASPP 相互作用。LinkTer 肽对蛋白水解的稳定性增加，穿透癌细胞，导致核收缩，并损害细胞活力。我们得出结论，仅由肽序列的 IDR 组成的设计肽可以作为一种改进的抑制剂，因为它不需要预折叠即可结合其靶蛋白，为 IDR 的治疗靶向铺平了道路。
