Department of Chemistry, Scripps Research, La Jolla, CA 92037.
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
Proc Natl Acad Sci U S A. 2021 Feb 23;118(8). doi: 10.1073/pnas.2005164118.
Site-selective chemical bioconjugation reactions are enabling tools for the chemical biologist. Guided by a careful study of the selenomethionine (SeM) benzylation, we have refined the reaction to meet the requirements of practical protein bioconjugation. SeM is readily introduced through auxotrophic expression and exhibits unique nucleophilic properties that allow it to be selectively modified even in the presence of cysteine. The resulting benzylselenonium adduct is stable at physiological pH, is selectively labile to glutathione, and embodies a broadly tunable cleavage profile. Specifically, a 4-bromomethylphenylacetyl (BrMePAA) linker has been applied for efficient conjugation of complex organic molecules to SeM-containing proteins. This expansion of the bioconjugation toolkit has broad potential in the development of chemically enhanced proteins.
位点选择性化学生物共轭反应是化学生物学家的有力工具。通过对硒代蛋氨酸（SeM）苄基化的仔细研究，我们对反应进行了改进，以满足实际蛋白质生物共轭的要求。SeM 可以通过营养缺陷型表达轻易引入，并表现出独特的亲核性质，即使在半胱氨酸存在的情况下也能进行选择性修饰。所得苄基硒翁加合物在生理 pH 下稳定，对谷胱甘肽选择性不稳定，并具有广泛可调的裂解特性。具体来说，已将 4-溴甲基苯乙酰基（BrMePAA）接头应用于将复杂有机分子有效连接到含 SeM 的蛋白质上。该生物共轭工具包的扩展在化学增强蛋白的开发中具有广泛的潜力。
