Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, Uppsala University, Biomedical Center, Uppsala, Sweden.
Med Res Rev. 2015 May;35(3):464-519. doi: 10.1002/med.21323. Epub 2014 Jun 3.
The proteolytic processing of neuropeptides has an important regulatory function and the peptide fragments resulting from the enzymatic degradation often exert essential physiological roles. The proteolytic processing generates, not only biologically inactive fragments, but also bioactive fragments that modulate or even counteract the response of their parent peptides. Frequently, these peptide fragments interact with receptors that are not recognized by the parent peptides. This review discusses tachykinins, opioid peptides, angiotensins, bradykinins, and neuropeptide Y that are present in the central nervous system and their processing to bioactive degradation products. These well-known neuropeptide systems have been selected since they provide illustrative examples that proteolytic degradation of parent peptides can lead to bioactive metabolites with different biological activities as compared to their parent peptides. For example, substance P, dynorphin A, angiotensin I and II, bradykinin, and neuropeptide Y are all degraded to bioactive fragments with pharmacological profiles that differ considerably from those of the parent peptides. The review discusses a selection of the large number of drug-like molecules that act as agonists or antagonists at receptors of neuropeptides. It focuses in particular on the efforts to identify selective drug-like agonists and antagonists mimicking the effects of the endogenous peptide fragments formed. As exemplified in this review, many common neuropeptides are degraded to a variety of smaller fragments but many of the fragments generated have not yet been examined in detail with regard to their potential biological activities. Since these bioactive fragments contain a small number of amino acid residues, they provide an ideal starting point for the development of drug-like substances with ability to mimic the effects of the degradation products. Thus, these substances could provide a rich source of new pharmaceuticals. However, as discussed herein relatively few examples have so far been disclosed of successful attempts to create bioavailable, drug-like agonists or antagonists, starting from the structure of endogenous peptide fragments and applying procedures relying on stepwise manipulations and simplifications of the peptide structures.
神经肽的蛋白水解加工具有重要的调节功能，酶降解产生的肽片段通常发挥重要的生理作用。蛋白水解加工不仅产生无生物活性的片段，还产生生物活性片段，这些片段可以调节甚至拮抗其母体肽的反应。这些肽片段经常与母体肽不能识别的受体相互作用。本文讨论了存在于中枢神经系统中的激肽、阿片肽、血管紧张素、缓激肽和神经肽 Y 及其加工为生物活性降解产物。选择这些众所周知的神经肽系统是因为它们提供了说明性的例子，即母体肽的蛋白水解降解可以导致具有与母体肽不同生物学活性的生物活性代谢物。例如，P 物质、强啡肽 A、血管紧张素 I 和 II、缓激肽和神经肽 Y 均降解为具有与母体肽的药理学特征差异很大的生物活性片段。本文讨论了大量作为神经肽受体激动剂或拮抗剂的类药分子。它特别侧重于确定模拟内源性肽片段形成的作用的选择性类药激动剂和拮抗剂的努力。如本文所述，许多常见的神经肽被降解为多种较小的片段，但许多生成的片段尚未详细研究其潜在的生物学活性。由于这些生物活性片段含有少量氨基酸残基，因此它们为开发具有模拟降解产物作用能力的类药物质提供了理想的起点。因此，这些物质可以为新药物提供丰富的来源。然而，正如本文所讨论的，迄今为止，从内源性肽片段的结构出发，应用依赖于肽结构逐步操作和简化的程序，成功创建生物可用的类药激动剂或拮抗剂的例子相对较少。
