Druggability of Phospholipase C-β Isoforms with Small Peptides Patterned after the Autoinhibitory XY Linker

The phospholipase C-β (PLCβ) signaling pathway plays a pivotal role in peripheral nociception, particularly during inflammation and pain transduction. Despite their validation as important therapeutic targets, PLCβ isoforms are yet undruggable due to the difficulties to identify potent and selective modulators. Here, we addressed this question and used 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 inhibited PIP2 hydrolysis and the consequent calcium release from endoplasmic reticulum. In primary nociceptor cultures, active peptides notably attenuated bradykinin-induced electrogenesis and TRPV1 sensitization, thus reducing nociceptor hyperexcitability. Noteworthy, intraplantar administration of a lead peptide prevented inflammation and hypersensitivity in a mouse model of inflammatory pain. Collectively, our findings indicate that peptides patterned after the autoinhibitory XY linker act as selective PLCβ inhibitors with in vivo anti-inflammatory and antinociceptive activity, providing pharmacological tools for this enzyme family.