Elucidation on the In Vivo Activity of the Bivalent Opioid Peptide MACE2 against Several Types of Chronic Pain

Biphalin is a bivalent μ/δ opioid receptor agonist showing a promising therapeutic profile with reduced side effects, but as a peptide is limited by poor metabolic stability and blood-brain barrier penetration. To improve these features, we developed the ligand MACE2 and showed initial in vivo efficacy. To further explore the druggability of this ligand, in this report, we tested MACE2 metabolic stability in human plasma, receptor engagement by 3 different routes of administration using the tail-flick test, and MACE2 efficacy in 2 different pathological and chronic pain models. We found that MACE2 had high stability in plasma and could produce target engagement and a tail flick response. We also showed that MACE2 had high analgesic efficacy in CIPN but no efficacy in paw incision. Together, these findings suggest that MACE2 has improved metabolic stability and brain penetration in vivo, prompting further development in clinical testing.