CLCC Eugène Marquis, Equipe Ligue Contre Le Cancer, Rennes, France.
Université Rennes, INSERM, UMR1242, Rennes, France.
Nat Chem Biol. 2018 Dec;14(12):1079-1089. doi: 10.1038/s41589-018-0162-9. Epub 2018 Nov 14.
CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca response via docking of PLCγ1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLCγ1 interaction. A structure-activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLCγ1. Thus, we synthesized CID peptidomimetics abrogating both the CD95-driven Ca response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients.
CD95L 是一种跨膜配体（m-CD95L），可被金属蛋白酶切割以释放可溶性配体（s-CD95L）。与 m-CD95L 不同，s-CD95L 与 CD95 之间的相互作用无法招募半胱天冬酶-8 和 FADD 来触发细胞凋亡，而是通过 PLCγ1 与 CD95 内的钙诱导结构域（CID）对接来诱导 Ca 反应。该信号通路诱导狼疮患者受损器官中炎症性 Th17 细胞的积累，从而加重疾病病理学。大规模筛选显示，HIV 蛋白酶抑制剂利托那韦是一种有效的 CD95-PLCγ1 相互作用破坏剂。构效关系方法强调，利托那韦是一种肽模拟物，在与 PLCγ1 对接方面与 CID 具有结构特征。因此，我们合成了 CID 肽模拟物，阻断了 CD95 驱动的 Ca 反应和 Th17 细胞的迁移。将利托那韦和 CID 肽模拟物注射到狼疮小鼠中，缓解了临床症状，为狼疮患者的药物治疗开辟了新途径。
