CLCC Eugène Marquis, INSERM, Univ Rennes 1, UMR1242, rue Bataille Flandres Dunkerque, 35042 Rennes, France; Equipe Ligue Contre Le Cancer, rue Bataille Flandres Dunkerque, 35042 Rennes, France.
Université de Bordeaux, 146 rue Léo Saignat, 33076 Bordeaux, France; INSERM U1218, 229 cours de l'Argonne, 33076 Bordeaux Cedex, France.
Bioorg Med Chem Lett. 2019 Aug 15;29(16):2094-2099. doi: 10.1016/j.bmcl.2019.07.006. Epub 2019 Jul 5.
The death receptor CD95 (also known as Fas) induces apoptosis through protein/protein association and the formation of the death-inducing signaling complex. On the other hand, in certain biological conditions, this receptor recruits different proteins and triggers the formation of another complex designated motility-inducing signaling complex, which promotes cell migration and inflammation. This pathway relies on a short sequence of CD95, called calcium-inducing domain (CID), which interacts with the phospholipase PLCγ1. To better understand how CID/PLCγ1 interaction occurs, we synthesized different α-AA peptides mimicking CID. Some of these peptidomimetics are as potent as the natural peptide to disrupt the CID/PLCγ1 interaction and cell migration, and showed improved pharmacokinetic properties. We also generated biotinyl- and palmitoyl-labelled peptidomimetics, useful chemico-biological tools to further explore the pro-inflammatory signal of CD95, which plays an important role in the pathogenesis of lupus and other autoimmune diseases.
死亡受体 CD95（也称为 Fas）通过蛋白/蛋白相互作用和形成死亡诱导信号复合物来诱导细胞凋亡。另一方面，在某些生物学条件下，该受体招募不同的蛋白质并触发另一种称为运动诱导信号复合物的形成，从而促进细胞迁移和炎症。该途径依赖于 CD95 的短序列，称为钙诱导结构域 (CID)，其与磷脂酶 PLCγ1 相互作用。为了更好地理解 CID/PLCγ1 相互作用是如何发生的，我们合成了不同的模拟 CID 的 α-AA 肽。其中一些肽模拟物与天然肽一样有效，可破坏 CID/PLCγ1 相互作用和细胞迁移，并显示出改善的药代动力学特性。我们还生成了生物素化和棕榈酰化的肽模拟物，这是有用的化学生物学工具，可进一步探索 CD95 的促炎信号，该信号在狼疮和其他自身免疫性疾病的发病机制中起重要作用。
