PDF(Pubmed)
Abstract：
(1) Autophagy plays a significant role in development and cell proliferation. This process is mainly accomplished by the LC3 protein, which, after maturation, builds the nascent autophagosomes. The inhibition of LC3 maturation results in the interference of autophagy activation. (2) In this study, starting from the structure of a known LC3B binder (LIR2-RavZ peptide), we identified new LC3B ligands by applying an in silico drug design strategy. The most promising peptides were synthesized, biophysically assayed, and biologically evaluated to ascertain their potential antiproliferative activity on five humans cell lines. (3) A cyclic peptide (named Pep6), endowed with high conformational stability (due to the presence of a disulfide bridge), displayed a Kd value on LC3B in the nanomolar range. Assays accomplished on PC3, MCF-7, and A549 cancer cell lines proved that Pep6 exhibited cytotoxic effects comparable to those of the peptide LIR2-RavZ, a reference LC3B ligand. Furthermore, it was ineffective on both normal prostatic epithelium PNT2 and autophagy-defective prostate cancer DU145 cells. (4) Pep6 can be considered a new autophagy inhibitor that can be employed as a pharmacological tool or even as a template for the rational design of new small molecules endowed with autophagy inhibitory activity.
摘要：
(1)自噬在发育和细胞增殖中起重要作用。这个过程主要由LC3蛋白完成,which,成熟后,建立新生的自噬体。LC3成熟的抑制导致自噬激活的干扰。(2)在这项研究中,从已知的LC3B结合剂（LIR2-RavZ肽）的结构开始，我们通过应用计算机模拟药物设计策略鉴定了新的LC3B配体。合成了最有前途的肽，生物物理测定，并进行生物学评估，以确定它们对五种人类细胞系的潜在抗增殖活性。（3）一种环肽（名为Pep6），具有高构象稳定性（由于二硫键的存在），在LC3B上显示的Kd值在纳摩尔范围内。在PC3，MCF-7和A549癌细胞系上完成的试验证明，Pep6表现出与LIR2-RavZ肽相当的细胞毒性作用，参考LC3B配体。此外，它对正常前列腺上皮PNT2和自噬缺陷前列腺癌DU145细胞均无效。（4）Pep6可以被认为是一种新的自噬抑制剂，可以用作药理学工具，甚至可以用作合理设计具有自噬抑制活性的新小分子的模板。
