Department of Chemistry, University of California , Berkeley, California 94720, United States.
Materials Sciences Division, Lawrence Berkeley National Laboratories , Berkeley, California 94720, United States.
J Am Chem Soc. 2017 Jul 19;139(28):9691-9697. doi: 10.1021/jacs.7b05164. Epub 2017 Jul 7.
Azide-alkyne cycloaddition is a powerful reaction for the formation of bioconjugates. When catalyzed by Cu(I) or strain promotion, this cycloaddition is considered to be a "click" reaction with many applications in chemical biology and materials science. We report a new type of azide-alkyne click chemistry for the synthesis of protein conjugates using cucurbit[6]uril (CB6) supramolecular chemistry. CB6-promoted azide-alkyne cycloaddition has been previously used for the synthesis of rotaxanes but has not been applied to the development of complex bioconjugates. By developing new substrates for CB6 click that do not contain any cross-reactive functional groups and by optimizing reaction conditions, we converted CB6 click chemistry from a rotaxane synthesis tool into a useful bioconjugation technique. Using these new parameters, we synthesized a series of protein conjugates including protein-peptide, protein-DNA, protein-polymer, and protein-drug conjugates. We further demonstrated that CB6 click can be used in conjunction with strain-promoted azide-alkyne cycloaddition to generate distinct bioconjugates in protein mixtures. CB6 click is a promising new reaction for the development of protein conjugates and can be applied toward the synthesis of complex biomaterials for a wide range of applications.
叠氮-炔环加成反应是形成生物缀合物的一种强大反应。当被 Cu(I) 或应变促进时，这种环加成反应被认为是一种“点击”反应，在化学生物学和材料科学中有许多应用。我们报告了一种新型的叠氮-炔点击化学，用于使用葫芦[6]脲（CB6）超分子化学合成蛋白质缀合物。CB6 促进的叠氮-炔环加成反应以前曾用于轮烷的合成，但尚未应用于复杂生物缀合物的开发。通过开发不含任何交叉反应官能团的新型 CB6 点击底物，并优化反应条件，我们将 CB6 点击化学从轮烷合成工具转变为有用的生物缀合技术。使用这些新参数，我们合成了一系列蛋白质缀合物，包括蛋白质-肽、蛋白质-DNA、蛋白质-聚合物和蛋白质-药物缀合物。我们进一步证明，CB6 点击可以与应变促进的叠氮-炔环加成反应结合使用，在蛋白质混合物中生成不同的生物缀合物。CB6 点击是开发蛋白质缀合物的一种很有前途的新反应，可应用于广泛应用的各种复杂生物材料的合成。
