Department of Pharmacy - University of Naples "Federico II", 80134, Naples, Italy; Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040, Madrid, Spain.
Renal and Vascular Inflammation Group, Instituto de Investigacion Sanitaria-Fundacion Jimenez Diaz (IIS-FJD), Autonoma University of Madrid (UAM), 28040, Madrid, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28040, Madrid, Spain.
Eur J Med Chem. 2021 Oct 5;221:113547. doi: 10.1016/j.ejmech.2021.113547. Epub 2021 May 14.
Herein we investigated the structural and cellular effects ensuing from the cyclization of a potent inhibitor of JAK2 as mimetic of SOCS1 protein, named PS5. The introduction of un-natural residues and a lactam internal bridge, within SOCS1-KIR motif, produced candidates that showed high affinity toward JAK2 catalytic domain. By combining CD, NMR and computational studies, we obtained valuable models of the interactions of two peptidomimetics of SOCS1 to deepen their functional behaviors. Notably, when assayed for their biological cell responses mimicking SOCS1 activity, the internal cyclic PS5 analogues demonstrated able to inhibit JAK-mediated tyrosine phosphorylation of STAT1 and to reduce cytokine-induced proinflammatory gene expression, oxidative stress generation and cell migration. The present study well inserts in the field of low-molecular-weight proteomimetics with improved longtime cellular effects and adds a new piece to the puzzled way for the conversion of bioactive peptides into drugs.
在此，我们研究了一种强效 JAK2 抑制剂 PS5 环化后产生的结构和细胞效应，该抑制剂模拟了 SOCS1 蛋白。在 SOCS1-KIR 基序内引入非天然残基和内酰胺桥，产生了对 JAK2 催化结构域具有高亲和力的候选物。通过结合 CD、NMR 和计算研究，我们获得了两种 SOCS1 肽模拟物相互作用的有价值模型，以深入了解它们的功能行为。值得注意的是，当检测它们模拟 SOCS1 活性的生物细胞反应时，内部环状 PS5 类似物能够抑制 JAK 介导的 STAT1 酪氨酸磷酸化，并降低细胞因子诱导的促炎基因表达、氧化应激产生和细胞迁移。本研究很好地插入了小分子蛋白质模拟物领域，具有改善的长时间细胞效应，并为将生物活性肽转化为药物的困惑途径增添了新的内容。
