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

近年来，阿片类药物滥用的增加导致过量死亡人数突然激增。此外，阿片类药物有许多副作用，如呼吸抑制、警觉性降低和依赖性。为了实现更安全的药理止痛疗法，需要开发活性范围有限的新药物类别。多肽对其靶分子具有高度的特异性，几乎不会在组织中积聚，因此可能引起较少的毒副作用。内源性阿片肽亮氨酸脑啡肽是阿片受体的天然配体，但由于其亲水性，无法通过血脑屏障到达靶点。此外，它在体内的停留时间只有几分钟。通过在N端连接一个疏水基团，我们能够稳定多肽并增加疏水性，使其能够运输到大脑中的目标分子。新开发的亮氨酸脑啡肽衍生物在体内先导研究中显示出更强的抗伤害感受活性，甚至超过了广泛使用的阿片类药物丁丙诺啡。为了使这种有希望的候选药物更接近于应用，必须对其作用机制和潜在的副作用进行进一步的研究。应在动物实验中研究与特定阿片受体拮抗剂的联合给药，以确定确切的作用部位。预期的脑内转运将通过血脑屏障的细胞培养模型进行研究。此外，不同的给药形式，如皮下给药和鼻腔给药，以及在创新的脂质纳米粒配方中的包封性，都应该进行比较。这种亮氨酸脑啡肽衍生物的详细研究和进一步开发可能使未来能够更定制、从而更安全的药理止痛。

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.