Salt Effect Accelerates Site-Selective Cysteine Bioconjugation.
Salt Effect Accelerates Site-Selective Cysteine Bioconjugation.
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DOI：
10.1021/acscentsci.6b00180
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发表时间：
2016-09-28
影响因子：
18.2
通讯作者：
Pentelute, Bradley L.
中科院分区：
文献类型：
--
作者：
Dai, Peng;Zhang, Chi;Welborn, Matthew;Shepherd, James J.;Zhu, Tianyu;Van Voorhis, Troy;Pentelute, Bradley L.
需要高效和选择性的化学反应。对于小分子化学，反应速率可以通过改变所用的浓度、温度和溶剂来改变。相反，对于大的生物分子，由于需要严格的生物相容性反应条件，因此难以通过调节这些变量来改变反应速率。在这里，我们表明，添加盐可以改变速率常数超过4个数量级的芳基化生物共轭反应之间的半胱氨酸残基的四个残基序列（π-钳）和全氟芳基亲电试剂。生物相容性硫酸铵显着提高反应速率，而不影响π-钳介导的芳基化的位点特异性，从而能够快速合成两种选择性杀死HER 2阳性乳腺癌细胞的位点特异性抗体药物缀合物。计算和结构-反应性研究表明，盐可以通过调节π-钳疏水侧链和亲电体之间的相互作用来调节反应速率。在此基础上，将盐效应推广到其他生物共轭化学中，发展了一种新的π-钳位半胱氨酸区域选择性烷基化反应。水溶液中的盐显著改变了π-钳介导的半胱氨酸生物缀合的反应速率，使得能够对包括抗体在内的蛋白质进行快速且位点特异性的修饰。盐对π-钳介导的芳基化的影响遵循Hofmeister系列。
Highly efficient and selective chemical reactions are desired. For small molecule chemistry, the reaction rate can be varied by changing the concentration, temperature, and solvent used. In contrast for large biomolecules, the reaction rate is difficult to modify by adjusting these variables because stringent biocompatible reaction conditions are required. Here we show that adding salts can change the rate constant over 4 orders of magnitude for an arylation bioconjugation reaction between a cysteine residue within a four-residue sequence (π-clamp) and a perfluoroaryl electrophile. Biocompatible ammonium sulfate significantly enhances the reaction rate without influencing the site-specificity of π-clamp mediated arylation, enabling the fast synthesis of two site-specific antibody–drug conjugates that selectively kill HER2-positive breast cancer cells. Computational and structure–reactivity studies indicate that salts may tune the reaction rate through modulating the interactions between the π-clamp hydrophobic side chains and the electrophile. On the basis of this understanding, the salt effect is extended to other bioconjugation chemistry, and a new regioselective alkylation reaction at π-clamp cysteine is developed. Salt in aqueous solution significantly changed the reaction rate of π-clamp mediated cysteine bioconjugation, enabling fast and site-specific modification of proteins including antibodies. The salt effect on π-clamp mediated arylation follows the Hofmeister series.
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影响因子：
8.4
作者：
Akkapeddi P;Azizi SA;Freedy AM;Cal PMSD;Gois PMP;Bernardes GJL
通讯作者：
Bernardes GJL
影响因子：
4.7
作者：
Agarwal, Paresh;Bertozzi, Carolyn R.
通讯作者：
Bertozzi, Carolyn R.
影响因子：
21.8
作者：
Lloyd, Gareth O.;Steed, Jonathan W.
通讯作者：
Steed, Jonathan W.
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
11.5
作者：
Hamblett, KJ;Senter, PD;Francisco, JA
通讯作者：
Francisco, JA