Disrupting the CD95–PLCγ1 interaction prevents Th17-driven inflammation

Investigation of Phospholipase Cγ1 Interaction with SLP76 Using Molecular Modeling Methods for Identifying Novel Inhibitors

“…Therefore, targeting the enzymes and receptors involved in regulation of cellular apoptosis has been established as an important therapeutic strategy for such pathological conditions [4,5,6,7,8,9,10,11,12]. Amongst the numerous regulators of apoptosis, the multifunctional phospholipase C (PLC) enzymes interact with target proteins to modulate the cellular apoptosis [13,14,15,16]. Indeed, PLCs are essential for regulation of several cellular processes as they catalyze the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) using Ca 2+ as cofactor [17].…”

“…The PLCγ1 isoform is constitutively expressed in all cells, whereas PLCγ2 is mainly expressed in immune cells [17]. Particularly, PLCγ1 has been identified to play an important role in the regulation of cell growth and cellular differentiation [17,19], by interacting with various macromolecular targets [17] such as epidermal growth factor, fibroblast growth factor, platelet derived growth factor, vascular endothelial growth factor and cluster of differentiation 95 (CD95) [16,21]. PLCγ1 is also known to be involved and to play an important role in cell invasion, metastasis and progression in cancers [13,15,22].…”

“…Using this information, Poissonnier et al have reported the design of an original peptidomimetic inhibitor, by employing molecular modeling studies [16]. In their work, protein-fragment complementation assay (PCA) and in vitro screening of 1280 molecules (Prestwick library) has been performed, identifying the inhibitors of PLCγ1–CD95 interactions which include ritonavir (HIV protease inhibitor), anethole (flavoring agent), daunorubicin (topoisomerase inhibitor), diflunisal (nonsteroidal anti-inflammatory drug), and rosiglitazone (antidiabetic agent which interacts with peroxisome proliferator-activated receptor) [16] (Figure 1). Additionally, a peptidomimetic (named DB550) (Figure 1) was designed on the basis of structural features extracted from the calcium inducing domain (CID) of CD95.…”

“…These inhibitors were demonstrated to specifically inhibit the interactions of PLCγ1 and CD95. Administration of both ritonavir and DB550 showed therapeutic effects in lupus-prone mice [16]. Overall these findings indicate that targeting the PLCγ1-SH3 is of prime importance for the management of various pathological conditions involving a plethora of immunological conditions and cancers.…”

Molecular design and optimization of hepatic cancer SLP76‐derived PLCγ1 SH3‐binding peptide with the systematic N‐substitution of peptide PXXP motif

“…Immunity is acquired when antibodies and T‐cell receptors are expressed and upregulated through the formation and release of lymphokines, chemokines, and cytokines, during which the phospholipase Cγ1 (PLCγ1) plays an essential role in T‐cell activation and development . Recently, Poissonnier and coworkers reported a successful application of designed peptidomimetics as potent competitive inhibitors to disrupt PLCγ1‐CD95 interaction for preventing Th17‐driven inflammation . The enzyme comprises two Src homology 2 (SH2) domains, one Src homology 3 (SH3) domain, one pleckstrin homology (PH) domain, and two catalytic domains (lipase and C2), which interacts with the adaptor proteins LAT and SLP76 through its SH2 and SH3 domains, respectively, resulting in formation of specific complexes that mediate T cell signaling …”