mPD5, an efficacious PICK1 inhibitor for treating chronic pain

Chronic 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 chronic pain. The myristoylated myr-NPEG4-(HWLKV)2, (mPD5), self-assembles core-shell micelles that provide favourable pharmacodynamic properties and relieves ongoing and evoked mechanical hypersensitivity, thermal hypersensitivity as well as anxio-depressive symptoms in an inflammatory pain model following subcutaneous administration. Further, mPD5 dose-dependently relieves pain in two neuropathic pain models without affecting motor behaviour. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceased after a few hours repeated administration provided pain relief lasting up to 20 hrs after last injection. ### Competing Interest Statement The lipidated dimeric peptides, their usage, and their extended utilization are disclosed in patent application WO2021/176094 currently being processed by patent authorities. KLM and ATS have ownership interest and are co-founders of Zyneyro, a company having exclusive license rights on the patent, which is owned by the University of Copenhagen, Denmark.