Rationally designed peptides relieve ischemic stroke by targeting TRPM2 intramolecular interactions

Area of Science:

• Molecular biology
• Neuroscience
• Pharmacology

Background:

• TRPM2 channels are calcium-permeable cation channels involved in oxidative stress sensing and pathologies like ischemic stroke.
• Current TRPM2 inhibitors lack specificity and efficacy due to targeting conserved regions.
• Targeting unique interfaces offers a novel strategy for developing selective ion channel inhibitors.

Purpose of the Study:

• To design and characterize a novel peptide inhibitor (M2IP) targeting the unique inter-subunit interface (interface III) of TRPM2.
• To evaluate the inhibitory potency, selectivity, and functional effects of M2IP on TRPM2.
• To assess the therapeutic potential of M2IP in a mouse model of ischemic stroke.

Main Methods:

• Peptide inhibitor design targeting TRPM2 interface III.
• In vitro assays for inhibitory potency and selectivity against TRP channels.
• Electrophysiology and calcium imaging to assess TRPM2 channel activity.
• In vivo evaluation in a mouse model of ischemic stroke.

Main Results:

• M2IP demonstrated sub-micromolar inhibitory potency and high selectivity for TRPM2 over other TRP channels.
• M2IP effectively suppressed TRPM2-mediated currents and calcium influx.
• M2IP treatment significantly alleviated brain injury in a mouse model of ischemic stroke.

Conclusions:

• M2IP is a potent and selective TRPM2 peptide inhibitor.
• Targeting unique inter-subunit interfaces is a viable strategy for developing specific ion channel therapeutics.
• M2IP shows therapeutic potential for treating ischemic stroke and other TRPM2-related pathologies.