The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia; School of Chemistry, University of Melbourne, Parkville, VIC 3010, Australia.
The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia.
Bioorg Med Chem. 2018 Jun 1;26(10):2827-2841. doi: 10.1016/j.bmc.2017.09.030. Epub 2017 Sep 27.
Peptidomimetics are designed to overcome the poor pharmacokinetics and pharmacodynamics associated with the native peptide or protein on which they are based. The design of peptidomimetics starts from developing structure-activity relationships of the native ligand-target pair that identify the key residues that are responsible for the biological effect of the native peptide or protein. Then minimization of the structure and introduction of constraints are applied to create the core active site that can interact with the target with high affinity and selectivity. Developing peptidomimetics is not trivial and often challenging, particularly when peptides' interaction mechanism with their target is complex. This review will discuss the challenges of developing peptidomimetics of therapeutically important insulin superfamily peptides, particularly those which have two chains (A and B) and three disulfide bonds and whose receptors are known, namely insulin, H2 relaxin, H3 relaxin, INSL3 and INSL5.
肽模拟物旨在克服与其所基于的天然肽或蛋白质相关的差的药代动力学和药效动力学。肽模拟物的设计始于开发天然配体-靶标对的结构-活性关系，确定负责天然肽或蛋白质生物学效应的关键残基。然后对结构进行最小化并引入约束，以创建可以与靶标高亲和力和选择性相互作用的核心活性位点。开发肽模拟物并不简单，通常具有挑战性，尤其是当肽与靶标的相互作用机制复杂时。本文将讨论开发治疗上重要的胰岛素超家族肽的肽模拟物的挑战，特别是那些具有两条链（A 和 B）和三个二硫键且其受体已知的肽模拟物，即胰岛素、H2 松弛素、H3 松弛素、INSL3 和 INSL5。
