mPD5, a peripherally restricted PICK1 inhibitor for treating chronic pain

Abstract

ABSTRACTChronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we develop and characterize a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assess its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2, (mPD5), self-assembles into core-shell micelles that provide favourable pharmacodynamic properties and relieves ongoing and evoked mechanical hypersensitivity, thermal hypersensitivity as well as anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt no side effects were associated with mPD5 administration, and it has no effect on acute nociception. Finally, neuropathic pain is relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceases after a few hours, repeated administration provides pain relief lasting up to 20 hours after the last injection.