Huhn Christiane, Maric Hans Michael
Rudolf Virchow Center for Integrative and Translational Bioimaging, Julius-Maximilians-Universität (JMU) Würzburg, Würzburg, Germany.
Methods Mol Biol. 2025;2934:233-243. doi: 10.1007/978-1-0716-4578-9_16.
Peptide libraries, especially those featuring cyclic and other modified variants, are central in drug discovery and chemical biology. Traditional methods for their generation often rely on labor-intensive synthetic approaches with limited diversity or enzyme-mediated conversions, which are constrained by substrate specificity, scalability challenges, complex biosynthetic systems, and restricted functional group diversity. This mini-review highlights enzymes from ribosomally synthesized and posttranslationally modified peptide (RiPP) gene clusters, an expanding class of biocatalysts, as a alternative enzyme source. RiPP enzymes may address key limitations in modified peptide library production, particularly in cyclization. With regulatable allosteric activities and compatibility with short synthetic peptides under mild conditions, these enzymes could be seamlessly integrated into scalable, high-throughput workflows and in vitro systems. This mini-review provides a perspective on RiPP enzymes through the lens of synthetic peptide library users, exploring their potential for converting synthetic peptide libraries and outlining the key requirements for their broader application in generating chemically diverse, new-to-nature peptide scaffolds.
肽库，尤其是那些具有环状和其他修饰变体的肽库，在药物发现和化学生物学中至关重要。传统的肽库生成方法通常依赖于劳动密集型的合成方法，其多样性有限，或者依赖于酶介导的转化，而酶介导的转化受到底物特异性、可扩展性挑战、复杂的生物合成系统以及有限的官能团多样性的限制。本综述重点介绍了核糖体合成和翻译后修饰肽（RiPP）基因簇中的酶，这是一类不断扩展的生物催化剂，可作为替代酶源。RiPP酶可能解决修饰肽库生产中的关键限制，特别是在环化方面。由于具有可调节的变构活性且在温和条件下与短合成肽兼容，这些酶可以无缝集成到可扩展的高通量工作流程和体外系统中。本综述从合成肽库用户的角度对RiPP酶进行了展望，探讨了它们转化合成肽库的潜力，并概述了其在生成化学多样性的新型天然肽支架中更广泛应用的关键要求。
