RNA Display Methods for the Discovery of Bioactive Macrocycles.,Chemical Reviews

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RNA Display Methods for the Discovery of Bioactive Macrocycles.
Chemical Reviews ( IF 51.4 ) Pub Date : 2018-11-05 , DOI: 10.1021/acs.chemrev.8b00430
Yichao Huang ₁ , Mareike Margarete Wiedmann ₁ , Hiroaki Suga ₁

Affiliation

The past two decades have witnessed the emergence of macrocycles, including macrocyclic peptides, as a promising yet underexploited class of de novo drug candidates. Both rational/computational design and in vitro display systems have contributed tremendously to the development of cyclic peptide binders of either traditional targets such as cell-surface receptors and enzymes or challenging targets such as protein-protein interaction surfaces. mRNA display, a key platform technology for the discovery of cyclic peptide ligands, has become one of the leading strategies that can generate natural-product-like macrocyclic peptide binders with antibody-like affinities. On the basis of the original cell-free transcription/translation system, mRNA display is highly evolvable to realize its full potential by applying genetic reprogramming and chemical/enzymatic modifications. In addition, mRNA display also allows the follow-up hit-to-lead development using high-throughput focused affinity maturation. Finally, mRNA-displayed peptides can be readily engineered to create chemical conjugates based on known small molecules or biologics. This review covers the birth and growth of mRNA display and discusses the above features of mRNA display with success stories and future perspectives and is up to date as of August 2018.

中文翻译：

用于发现生物活性大环化合物的RNA显示方法。

在过去的二十年中，包括大环肽在内的大环化合物出现了，作为一种有前途但尚未得到充分利用的从头药物候选物。合理/计算设计和体外展示系统都为开发传统靶标（例如细胞表面受体和酶）或挑战性靶标（例如蛋白质-蛋白质相互作用表面）的环状肽结合剂做出了巨大贡献。mRNA展示是发现环肽配体的关键平台技术，已成为可以生成具有抗体亲和力的天然产物样大环肽结合剂的主要策略之一。在原始的无细胞转录/翻译系统的基础上，通过应用基因重编程和化学/酶促修饰，mRNA展示可高度发展以发挥其全部潜力。此外，mRNA展示还允许使用高通量聚焦亲和力成熟技术进行后续的“铅到铅”开发。最后，基于已知的小分子或生物制剂，可以很容易地对展示mRNA的肽进行改造，以产生化学偶联物。这篇综述涵盖了mRNA展示的诞生和发展，并讨论了mRNA展示的上述功能以及成功案例和未来展望，截至2018年8月。基于已知的小分子或生物制剂，可以很容易地对mRNA展示的肽进行改造，以产生化学偶联物。这篇综述涵盖了mRNA展示的诞生和发展，并讨论了mRNA展示的上述功能以及成功案例和未来展望，截至2018年8月。基于已知的小分子或生物制剂，可以很容易地对mRNA展示的肽进行改造，以产生化学偶联物。这篇综述涵盖了mRNA展示的诞生和发展，并讨论了mRNA展示的上述功能以及成功案例和未来展望，截至2018年8月。

更新日期：2018-11-05

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