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.
Bioconjug Chem. 2024 Mar 20;35(3):286-299. doi: 10.1021/acs.bioconjchem.3c00447. Epub 2024 Mar 7.
Chemoselective protein modification plays extremely important roles in various biological, medical, and pharmaceutical investigations. Mimicking the mechanism of the chemoselective reaction between natural azaphilones and primary amines, this work successfully simplified the azaphilone scaffold into much simpler 3-acyl-4-pyranones. Examinations confirmed that these slim-size mimics perfectly kept the unique reactivity for selective conjugation with the primary amines including lysine residues of peptides and proteins. The newly developed pyranone tool presents remarkably increased aqueous solubility and compatible second-order rate constant by comparison with the original azaphilone. Additional advantages also include the ease of biorthogonal combinative use with a copper-catalyzed azide-alkyne Click reaction, which was conveniently applied to decorate lysozyme with neutral-, positive- and negative-charged functionalities in parallel. Moderate-degree modification of lysozyme with positively charged quaternary ammoniums was revealed to increase the enzymatic activities.
化学选择性蛋白质修饰在各种生物、医学和药物研究中起着极其重要的作用。本工作模拟天然氮杂菲酮与伯胺之间的化学选择性反应机制，成功地将氮杂菲酮支架简化为更简单的 3-酰基-4-吡喃酮。研究证实，这些瘦身模拟物完美地保持了与包括肽和蛋白质的赖氨酸残基在内的伯胺选择性共轭的独特反应性。与原始氮杂菲酮相比，新开发的吡喃酮工具具有显著增加的水溶解度和相容的二级速率常数。额外的优点还包括与铜催化的叠氮-炔点击反应方便地进行双正交组合使用，这可以方便地用于同时修饰溶菌酶的中性、正电荷和负电荷功能。适度修饰带正电荷的季铵盐的溶菌酶被证明可以提高酶活性。
