Wei Siyuan, Zhang Xuchun, Yang Xiaoliang, Liu Fa, Yao Zhu-Jun
State Key Laboratory of Coordination Chemistry, and Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China.
Nat Chem. 2025 Aug 6. doi: 10.1038/s41557-025-01896-8.
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.
将非天然氨基酸（如位阻N-甲基化或α,α-二取代氨基酸）引入肽中，可以改善其在制药和生物医学领域应用的性能。然而，当前的固相肽合成（SPPS）在引入位阻氨基酸时面临反应速率缓慢和产率低的问题，这是由于从溶液到固体的两相酰基转移过程动力学较差。在此，我们引入一种固定化的核糖体模拟分子反应器，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，并提高了含N-甲基化和/或α,α-二取代氨基酸的位阻肽（包括环孢菌素A和短杆菌肽F类似物）固相合成中的偶联效率。核糖体模拟分子反应器SPPS可以使用市售树脂和试剂整合到现有的SPPS平台中，并与标准合成仪具有高度兼容性，从而能够自动合成药学上重要的、位阻大的难合成肽。
