| Literature DB >> 30429604 |
Amanda Poissonnier1,2, Jean-Philippe Guégan1,2, Ha Thanh Nguyen1,2, Daniel Best1,2,3, Nicolas Levoin4, Guennadi Kozlov5, Kalle Gehring5, Raphael Pineau1,2, Florence Jouan1,2, Lucie Morere1,2, Sophie Martin1,2, Mélissa Thomas1,2, Estibaliz Lazaro6,7,8, Isabelle Douchet5,7, Thomas Ducret6,9, Pierre van de Weghe1,2, Patrick Blanco6,7,8, Mickael Jean1,2, Pierre Vacher6,10, Patrick Legembre11,12.
Abstract
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 Ca2+ 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 Ca2+ 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.Entities:
Mesh：
Substances：
Year: 2018 PMID： 30429604 DOI： 10.1038/s41589-018-0162-9
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040