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、警惕性降低和依赖性。为了实现更安全的疼痛药物治疗，需要开发具有有限活性谱的新药物类别。多肽对其靶分子具有高特异性，在组织中几乎不积累，因此潜在的毒副作用较小。内源性阿片肽Leu-enkephalin是阿片受体的天然配体，但由于其亲水性，它不能穿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端偶联疏水性基团，我们能够稳定肽并充分增加疏水性，从而允许运输到大脑中的目标分子。新开发的Leu-enkephalin衍生物在体内初步研究中显示出增加的抗痛觉活性，甚至优于广泛使用的阿片类药物丁丙诺啡。为了使这种有前途的候选药物更接近应用，必须对其作用机制和潜在副作用进行进一步的研究。为了确定确切的作用部位，应在动物实验中研究与特定阿片受体拮抗剂联合给药。预期的脑运输将通过血脑屏障的细胞培养模型进行研究。此外，应该比较不同形式的给药，如皮下和鼻内给药，以及在创新的脂质纳米颗粒配方中的包封。详细的研究和进一步开发这种Leu-Enkephalin衍生物可以在未来实现更个性化和更安全的药物疼痛管理。

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.