Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen 9747 AG, The Netherlands.
FEMS Microbiol Rev. 2023 May 19;47(3). doi: 10.1093/femsre/fuad017.
Natural bioactive peptide discovery is a challenging and time-consuming process. However, advances in synthetic biology are providing promising new avenues in peptide engineering that allow for the design and production of a large variety of new-to-nature peptides with enhanced or new bioactivities, using known peptides as templates. Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs). The modularity of post-translational modification (PTM) enzymes and ribosomal biosynthesis inherent to lanthipeptides enables their engineering and screening in a high-throughput manner. The field of RiPPs research is rapidly evolving, with many novel PTMs and their associated modification enzymes being identified and characterized. The modularity presented by these diverse and promiscuous modification enzymes has made them promising tools for further in vivo engineering of lanthipeptides, allowing for the diversification of their structures and activities. In this review, we explore the diverse modifications occurring in RiPPs and discuss the potential applications and feasibility of combining various modification enzymes for lanthipeptide engineering. We highlight the prospect of lanthipeptide- and RiPP-engineering to produce and screen novel peptides, including mimics of potent non-ribosomally produced antimicrobial peptides (NRPs) such as daptomycin, vancomycin, and teixobactin, which offer high therapeutic potential.
天然生物活性肽的发现是一个具有挑战性和耗时的过程。然而，合成生物学的进步为肽工程提供了有前景的新途径，允许使用已知的肽作为模板来设计和生产具有增强或新的生物活性的各种新型天然肽。硫肽是核糖体合成和翻译后修饰的肽（RiPPs）。翻译后修饰（PTM）酶和硫肽固有的核糖体生物合成的模块化使其能够以高通量的方式进行工程化和筛选。RiPPs 研究领域正在迅速发展，许多新的 PTM 及其相关修饰酶被鉴定和表征。这些多样化和混杂的修饰酶所呈现的模块化使其成为进一步体内工程化硫肽的有前途的工具，允许其结构和活性的多样化。在这篇综述中，我们探讨了 RiPPs 中发生的各种修饰，并讨论了结合各种修饰酶进行硫肽工程的潜在应用和可行性。我们强调了利用硫肽和 RiPP 工程来生产和筛选新型肽的前景，包括模仿强效非核糖体产生的抗菌肽（NRPs），如达托霉素、万古霉素和 Teixobactin，它们具有很高的治疗潜力。
