State Key Laboratory of Coordination Chemistry and Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, Nanjing, Jiangsu, 210023, China.
Angew Chem Int Ed Engl. 2022 Feb 1;61(6):e202111783. doi: 10.1002/anie.202111783. Epub 2021 Dec 21.
Residue-selective bioconjugation methods for biomolecules are highly sought to expand the scope of their biological and medical applications. Inspired by the mechanism of the generation of natural vinylogous γ-pyridones (vPDNs), we have developed a novel unique azaphilone-based, activation-free primary-amine-selective bioconjugation method for biomolecules. Our strategy allows facile functionalization of primary amine groups in peptides and proteins, including the clinically used therapeutic antibody trastuzumab, by generating a highly stable vPDN linkage. Excellent chemoselectivity toward primary amines also enables the azaphilone derivatives to specifically modify the lipid components of Gram-positive bacteria while bypassing Gram-negative bacteria and mammalian cells. The new method shows significant advantages including chemoselectivity, efficiency, flexibility and biocompatibility, and therefore provides a valuable addition to the current toolbox for biomolecule conjugation.
为了拓展生物分子的生物医学应用范围，人们迫切需要开发针对生物分子的选择性残留生物偶联方法。受天然乙烯基γ-吡啶酮（vPDN）生成机制的启发，我们开发了一种新型独特的基于氮杂菲酮的、无需活化的、对伯胺具有选择性的生物分子偶联方法。该策略可以方便地对肽和蛋白质中的伯胺基团进行功能化，包括临床使用的治疗性抗体曲妥珠单抗，生成高度稳定的 vPDN 键。该氮杂菲酮衍生物对伯胺具有优异的化学选择性，使其能够特异性修饰革兰氏阳性菌的脂质成分，而不会与革兰氏阴性菌和哺乳动物细胞发生反应。该新方法具有化学选择性、效率、灵活性和生物相容性等显著优势，因此为生物分子偶联的现有工具包提供了有价值的补充。
