Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois (K.D.B.A., E.V.R., J.V.S.) and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska (J.W.C.).
Department of Chemistry and the Beckman Institute for Advanced Science and Technology, University of Illinois Urbana-Champaign, Urbana, Illinois (K.D.B.A., E.V.R., J.V.S.) and Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska (J.W.C.)
Pharmacol Rev. 2022 Jul;74(3):662-679. doi: 10.1124/pharmrev.121.000423.
The discovery of insulin in the early 1900s ushered in the era of research related to peptides acting as hormones and neuromodulators, among other regulatory roles. These essential gene products are found in all organisms, from the most primitive to the most evolved, and carry important biologic information that coordinates complex physiology and behavior; their misregulation has been implicated in a variety of diseases. The evolutionary origins of at least 30 neuropeptide signaling systems have been traced to the common ancestor of protostomes and deuterostomes. With the use of relevant animal models and modern technologies, we can gain mechanistic insight into orthologous and paralogous endogenous peptides and translate that knowledge into medically relevant insights and new treatments. Groundbreaking advances in medicine and basic science influence how signaling peptides are defined today. The precise mechanistic pathways for over 100 endogenous peptides in mammals are now known and have laid the foundation for multiple drug development pipelines. Peptide biologics have become valuable drugs due to their unique specificity and biologic activity, lack of toxic metabolites, and minimal undesirable interactions. This review outlines modern technologies that enable neuropeptide discovery and characterization, and highlights lessons from nature made possible by neuropeptide research in relevant animal models that is being adopted by the pharmaceutical industry. We conclude with a brief overview of approaches/strategies for effective development of peptides as drugs. SIGNIFICANCE STATEMENT: Neuropeptides, an important class of cell-cell signaling molecules, are involved in maintaining a range of physiological functions. Since the discovery of insulin's activity, over 100 bioactive peptides and peptide analogs have been used as therapeutics. Because these are complex molecules not easily predicted from a genome and their activity can change with subtle chemical modifications, mass spectrometry (MS) has significantly empowered peptide discovery and characterization. This review highlights contributions of MS-based research towards the development of therapeutic peptides.
20 世纪初胰岛素的发现开创了与作为激素和神经调节剂发挥作用的肽相关的研究时代，这些肽还具有其他调节作用。这些基本的基因产物存在于所有生物体中，从最原始到最进化的生物体，携带协调复杂生理和行为的重要生物信息；它们的失调与多种疾病有关。至少 30 种神经肽信号系统的进化起源可以追溯到原口动物和后口动物的共同祖先。通过使用相关的动物模型和现代技术，我们可以深入了解同源和旁系同源的内源性肽，并将这些知识转化为具有医学相关性的见解和新的治疗方法。医学和基础科学的突破性进展影响了当今对信号肽的定义。目前已知哺乳动物中超过 100 种内源性肽的确切机制途径，为多个药物开发渠道奠定了基础。由于其独特的特异性和生物活性、缺乏有毒代谢物以及最小的不良相互作用，肽类生物制剂已成为有价值的药物。本文概述了能够发现和鉴定神经肽的现代技术，并强调了通过相关动物模型进行的神经肽研究为制药行业所采用的自然启示，这些研究为神经肽的发现和鉴定提供了重要的线索。我们最后简要概述了将肽作为药物有效开发的方法/策略。
神经肽是一类重要的细胞间信号分子，参与维持多种生理功能。自胰岛素活性被发现以来，已有 100 多种生物活性肽和肽类似物被用作治疗药物。由于这些是复杂的分子，不易从基因组中预测，并且它们的活性可以随着微小的化学修饰而变化，因此质谱 (MS) 极大地增强了肽的发现和鉴定能力。这篇综述强调了基于 MS 的研究对治疗性肽的开发的贡献。
