Rationally designed peptides relieve ischemic stroke by targeting TRPM2 intramolecular interactions

TRPM2 is a calcium-permeable cation channel that functions as an oxidative stress sensor and plays a key role in various pathologies, particularly ischemic stroke. The activation of hsTRPM2 requires cooperative engagement of its N‑ and C‑terminal domains, a mechanism distinct among TRP channels. Existing small-molecule inhibitors, which primarily target conserved pore and ligand-binding regions, often suffer from limited specificity and poor efficacy, hampering their clinical translation. Therefore, we designed a TRPM2 peptide inhibitor (M2IP) by targeting the unique inter‑subunit interface (interface III) within TRPM2. M2IP exhibited sub‑micromolar inhibitory potency and high selectivity over other TRP channels. Electrophysiology and calcium imaging showed that it effectively suppressed TRPM2-mediated currents and calcium influx. In the mouse model of ischemic stroke, M2IP treatment significantly alleviated brain injury. This study not only develops M2IP as a potent and specific TRPM2 inhibitor, also sheds new light on developing peptide therapeutics against ion channels.