The development of potent, specific, and pharmacologically viable chemical probes and therapeutics is a central focus of chemical biology and therapeutic development. However, a significant portion of predicted disease-causal proteins have proven resistant to targeting by traditional small molecule and biologic modalities. Many of these so-called “undruggable” targets feature extended, dynamic protein–protein and protein–nucleic acid interfaces that are central to their roles in normal and diseased signaling pathways. Here, we discuss the development of synthetically stabilized peptide and protein mimetics as an ever-expanding and powerful region of chemical space to tackle undruggable targets. These molecules aim to combine the synthetic tunability and pharmacologic properties typically associated with small molecules with the binding footprints, affinities and specificities of biologics. In this review, we discuss the historical and emerging platforms and approaches to design, screen, select and optimize synthetic “designer” peptidomimetics and synthetic biologics. We examine the inspiration and design of different classes of designer peptidomimetics: (i) macrocyclic peptides, (ii) side chain stabilized peptides, (iii) non-natural peptidomimetics, and (iv) synthetic proteomimetics, and notable examples of their application to challenging biomolecules. Finally, we summarize key learnings and remaining challenges for these molecules to become useful chemical probes and therapeutics for historically undruggable targets.

中文翻译：

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用设计师拟肽药和合成生物制剂处理不可成药的靶点


开发有效、特异性和药理学上可行的化学探针和疗法是化学生物学和治疗开发的中心重点。然而，很大一部分预测的疾病致病蛋白已被证明对传统小分子和生物模式的靶向具有抗性。许多这些所谓的“不可成药”靶标具有扩展的动态蛋白质-蛋白质和蛋白质-核酸界面，这些界面是它们在正常和患病信号通路中发挥作用的核心。在这里，我们讨论了合成稳定的肽和蛋白质模拟物的发展，作为一个不断扩大和强大的化学空间区域，以解决不可成药的靶点。这些分子旨在将通常与小分子相关的合成可调性和药理学特性与生物制剂的结合足迹、亲和力和特异性相结合。在这篇综述中，我们讨论了设计、筛选、选择和优化合成 “设计师” 模拟肽和合成生物制剂的历史和新兴平台和方法。我们研究了不同类别的设计师肽模拟物的灵感和设计：（i） 大环肽，（ii） 侧链稳定肽，（iii） 非天然肽模拟物，和 （iv） 合成蛋白质模拟物，以及它们应用于具有挑战性的生物分子的显着例子。最后，我们总结了这些分子成为历史上无法成药的靶点的有用化学探针和治疗方法的关键知识和仍然存在的挑战。