Small peptides derived from the autoinhibitory XY linker of phospholipase C-β isoforms inhibit enzyme activity and reduce inflammation

Phospholipase C-β (PLCβ) signaling plays a pivotal role in peripheral nociception during inflammation and pain transduction. These enzymes are associated with G-protein coupled receptors of pro-inflammatory and algesic agents that sensitize nociceptors and promote their hyperexcitability. Despite their validation as therapeutic targets, PLCβ isoforms are yet considered undruggable due to the difficulties to identify potent and selective modulators. Here, we address this question and use the autoinhibitory XY linker present in these enzymes as a source of peptide inhibitors of PLCβ activity. We report that peptides patterned after this motif penetrate the cell membrane and interact with PLCβ3 to inhibit PIP₂ hydrolysis and the consequent calcium release from endoplasmic reticulum. These peptides selectively target PLCβ isoforms, without affecting PLCγ-dependent signaling. In primary nociceptor cultures, active peptides attenuate bradykinin-induced electrogenesis and TRPV1 sensitization reducing nociceptor hyperexcitability. Noteworthy, intraplantar administration of a lead peptide prevented inflammation and hypersensitivity in a mouse model of inflammatory pain, highlighting a therapeutic potential. Collectively, our findings indicate that peptides derived from the autoinhibitory XY linker act as selective PLCβ inhibitors with in vivo anti-inflammatory and antinociceptive activity, providing novel pharmacological tools for this enzyme family.