Ullrich Sven, Nitsche Christoph
Research School of Chemistry, Australian National University, Canberra, ACT, Australia.
Methods Mol Biol. 2025;2931:13-25. doi: 10.1007/978-1-0716-4562-8_2.
Constrained peptides are emerging as promising structures in therapeutic development. Offering compatibility with genetically encoded libraries for drug discovery, biocompatible methods to constrain peptides are particularly attractive. While there are many such methods to construct cyclic and stapled peptides, the biocompatible generation of bicyclic peptides is less explored. Addressing this need for biocompatible and selective ways to generate peptide bicycles, we previously developed a strategy based on noncanonical amino acids leveraging the reactivity of cyanopyridine and 1,2-aminothiol. This protocol provides detailed step-by-step instructions for the synthesis of these peptide bicycles and is designed to be accessible even to laboratories with limited synthetic chemistry resources. It outlines the solid-phase peptide synthesis of linear peptide precursors that efficiently form bicyclic structures in aqueous buffer at physiological pH. Utilizing commercially available building blocks, we devised a method to synthesize the noncanonical amino acids that are essential for bicyclization directly on the solid support during peptide synthesis.
受限肽正成为治疗药物开发中颇具前景的结构。由于与用于药物发现的基因编码文库具有兼容性，用于限制肽的生物相容性方法尤其具有吸引力。虽然有许多构建环肽和订书肽的方法，但双环肽的生物相容性生成研究较少。为满足对生成肽双环的生物相容性和选择性方法的需求，我们之前开发了一种基于非天然氨基酸的策略，利用氰基吡啶和1,2-氨基硫醇的反应性。本方案提供了这些肽双环合成的详细分步说明，即使是合成化学资源有限的实验室也可使用。它概述了线性肽前体的固相肽合成，该前体在生理pH值的水性缓冲液中能有效形成双环结构。利用市售的构件，我们设计了一种方法，可在肽合成过程中直接在固相载体上合成双环化所必需的非天然氨基酸。
