使用乙烯基砜作为硫醇迈克尔“点击”受体的树脂上缩环肽。
On-Resin Macrocyclization of Peptides Using Vinyl Sulfonamides as a Thiol-Michael "Click" Acceptor.
机构信息
Department of Materials Science and Engineering , University of Delaware , 201 DuPont Hall , Newark , Delaware 19716 , United States.
Department of Chemical and Biomolecular Engineering , University of Delaware , 150 Academy Street , Newark , Delaware 19716 , United States.
出版信息
Bioconjug Chem. 2018 Dec 19;29(12):3987-3992. doi: 10.1021/acs.bioconjchem.8b00751. Epub 2018 Nov 26.
Macrocyclization of linear peptides imparts improved stability to enzymatic degradation and increases potency of function. Many successful macrocyclization of peptides both in solution and on-resin have been achieved but are limited in scope as they lack selectivity, require long reaction times, or necessitate heat. To overcome these drawbacks a robust and facile strategy was developed employing thiol-Michael click chemistry via an N-methyl vinyl sulfonamide. We demonstrate its balance of reactivity and high stability through FTIR model kinetic studies, reaching 88% conversion over 30 min, and NMR stability studies, revealing no apparent degradation over an 8 day period in basic conditions. Using a commercially available reagent, 2-chloroethane sulfonyl chloride, the cell adhesion peptide, RGDS, was functionalized and macrocyclized on-resin with a relative efficiency of over 95%. The simplistic nature of this process demonstrates the effectiveness of vinyl sulfonamides as a thiol-Michael click acceptor and its applicability to many other bioconjugation applications.
线性肽的环化赋予其对酶降解的稳定性提高，并增加其功能的效力。已经实现了许多成功的肽的溶液和树脂上的环化，但它们的范围有限，因为它们缺乏选择性，需要长的反应时间，或需要加热。为了克服这些缺点，我们开发了一种稳健且简便的策略，通过 N-甲基乙烯基磺酰胺的硫醇-Michael 点击化学来实现。我们通过 FTIR 模型动力学研究证明了它的反应性和高稳定性之间的平衡，在 30 分钟内达到 88%的转化率，并通过 NMR 稳定性研究证明在碱性条件下 8 天内没有明显的降解。使用商业上可获得的试剂 2-氯乙磺酰氯，将细胞黏附肽 RGDS 进行了功能化，并在树脂上进行了大环化，相对效率超过 95%。该过程的简单性质证明了乙烯基磺酰胺作为硫醇-Michael 点击接受体的有效性，以及其在许多其他生物偶联应用中的适用性。
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