近日，南京大学姚祝军团队实现了固定化酰基转移分子反应器能够固相合成空间位阻肽。2025年8月6日出版的《自然-化学》杂志发表了这项成果。

将非天然氨基酸（如受阻N-甲基化或α，α-二取代氨基酸）掺入肽中可以改善其在制药和生物医学领域的应用。然而，由于两相酰基从溶液到固体的转移过程动力学不佳，目前固相肽合成（SPPS）在加入位阻氨基酸时面临反应速率缓慢和产率低的问题。

研究组介绍了一种固定化的模拟核糖体分子反应器，以促进树脂上邻近诱导的反应器内（间）酰基转移。该策略绕过了传统SPPS中的两相酰基转移机制，提高了固相合成含N-甲基化和/或α，α-二取代氨基酸(s)的立体受阻肽的偶联效率，包括环孢素A和alamethicin F类似物。该核糖体模拟分子反应器SPPS可以集成到现有的SPPS平台上，以市售树脂和试剂为主体，并与标准合成器具有高兼容性，能够自动合成具有重要药学意义的、立体受阻的难合成肽。

附：英文原文

Title: Immobilized acyl-transfer molecular reactors enable the solid-phase synthesis of sterically hindered peptides

Author: Wei, Siyuan, Zhang, Xuchun, Yang, Xiaoliang, Liu, Fa, Yao, Zhu-Jun

Issue&Volume: 2025-08-06

Abstract: Incorporating unnatural amino acids, such as hindered N-methylated or α,α-disubstituted amino acid(s), into peptides can improve their properties for application in the pharmaceutical and biomedical fields. However, the current solid-phase peptide synthesis (SPPS) faces sluggish reaction rates and low yields when incorporating sterically hindered amino acids, owing to the poor kinetics of the two-phase acyl-transfer process from solution to solid. Here we introduce an immobilized ribosome-mimicking molecular reactor to facilitate on-resin proximity-induced intra(inter)-reactor acyl transfers. This strategy bypasses the two-phase acyl-transfer mechanism in conventional SPPS and boosts coupling efficiency in the solid-phase synthesis of N-methylated and/or α,α-disubstituted amino acid(s)-containing sterically hindered peptides, including cyclosporin A and alamethicin F analogues. The ribosome-mimicking molecular reactor SPPS can be integrated into existing SPPS platforms using commercially available resins and reagents, and displays high compatibility with standard synthesizers, enabling the automated synthesis of pharmaceutically important, sterically hindered difficult peptides.

DOI: 10.1038/s41557-025-01896-8

Source: https://www.nature.com/articles/s41557-025-01896-8