CD95L is a transmembrane ligand (m-CD95L) releases a soluble ligand (s-CD95L) that is cleaved by metalloproteases. Unlike m-CD95L, the 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. Additionally, this signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology.

A study from Amanda Poissonnier discovered and identified a novel compound DB550, which targets PLCγ1 and disrupts the CD95-PLCγ 1 interaction. Interestingly, the authors also found that HIV protease inhibitor Ritonavir is a potent disruptor of the CD95-PLCγ1 interaction. Let’s get back to the novel compound DB550.

In the study, DB550 disrupted the CD95-PLCγ1 interaction without affecting the CD95-FADD interaction. Moreover, the authors conjugated it to biotin and performed a pull-down assay. Biotin-conjugated DB550 interacted with endogenous PLCγ1. Likewise, biotin-Ritonavir bound to PLCγ1. Both ritonavir and DB550 abrogated binding of PLCγ1 to CD95 in cells exposed to s-CD95L. Pre-trement of Th17 cells with DB550 inhibited the CD95-mediated Ca2+ response in a similar manner to minCID and prevented Th17 trafficking across endothelial cells. Of note, DB550 did not affect the CD95-mediated apoptotic signaling pathway

On the pharmacology, DB550 exhibited improved pharmacokinetic parameters, with a half-life in human blood equivalent to 11.1h; by contrast, the half-lives of the CID peptide and HT105 were around 3h. To sum up, DB550 is such a promising therapeutic drug and more biological experiments need to be carried out.

Poissonnier A, et al. Disrupting the CD95-PLCγ1 interaction prevents Th17-driven inflammation. Nat Chem Biol. 2018 Dec;14(12):1079-1089.