Development of a highly stable Leu-enkephalin derivative with improved antinociceptive activity

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In recent years, the increased abuse of opioids has led to a sudden surge of overdose deaths. In addition, opioids have numerous side effects such as respiratory depression, reduced vigilance, and dependency. The development of new drug classes with a limited spectrum of activity is required in order to enable safer pharmacological pain therapies. Peptides have a high specificity to their target molecule, hardly accumulate in the tissue and thus potentially cause less toxic side effects. The endogenous opioid peptide Leu-enkephalin is a natural ligand of the opioid receptors but due to its hydrophilic properties, it is unable to cross the blood-brain barrier and reach its target. In addition, it has a residence time in the body of only a few minutes. By conjugating a hydrophobic group at the N-terminus, we were able to stabilize the peptide and increase the hydrophobicity sufficiently to allow transport to the target molecule in the brain. The newly developed Leu-enkephalin derivative showed an increased antinociceptive activity in an in vivo pilot study, outperforming even the widely used opioid buprenorphine. Further studies on the mechanism of action and potential side effects must be carried out in order to bring this promising drug candidate closer to an application. A joint administration with antagonists of specific opioid receptors should be investigated in animal experiments in order to identify the exact site of action. The anticipated transport to the brain is to be investigated by a cell culture model of the blood-brain barrier. In addition, different forms of administration such as subcutaneous and intranasal administration should be compared as well as the encapsulation in an innovative lipid nanoparticle formulation. The detailed investigation and further development of such a Leu-Enkephalin derivative could enable a more customized and thus safer pharmacological pain management in the future.