Jongkees S A K, Umemoto S, Suga H
Department of Chemistry , Graduate School of Science , The University of Tokyo , 7-3-1 Hongo , 113-0033 Tokyo , Bunkyo-ku , Japan . Email:
JST CREST , The University of Tokyo , 7-3-1 Hongo , 113-0033 Tokyo , Bunkyo-ku , Japan.
Chem Sci. 2017 Feb 1;8(2):1474-1481. doi: 10.1039/c6sc04381j. Epub 2016 Oct 21.
We report a strategy for efficient post-translational modification of a library of ribosomally-translated peptides by activation and elimination of cysteine to dehydroalanine then conjugate addition of a range of exogenous thiols, with an emphasis on carbohydrates. These reactions are selective for cysteine, and do not interfere with amplification of the nucleic acid component of an mRNA-displayed peptide. Furthermore, these reactions are shown to be compatible with two different macrocyclisation chemistries, and when applied to a peptide containing an -terminal cysteine give a ketone that can be functionalised in an orthogonal manner. This new strategy can overcome a limitation of ribosomal translation, providing a means to incorporate untranslatable groups such as carbohydrates in amino acid side chains, and will allow for the ribosomal generation of glycopeptides, requiring only the introduction of a free thiol in the molecule to be incorporated. In combination with selection techniques, this strategy is envisaged to allow the discovery of biologically-active glycopeptides with a near-natural, but hydrolytically stable, thioglycosidic bond.
我们报道了一种策略，通过将半胱氨酸激活并消除生成脱氢丙氨酸，然后进行一系列外源硫醇（重点是碳水化合物）的共轭加成反应，对核糖体翻译的肽库进行高效的翻译后修饰。这些反应对半胱氨酸具有选择性，且不干扰mRNA展示肽中核酸成分的扩增。此外，这些反应被证明与两种不同的大环化化学方法兼容，当应用于含有N端半胱氨酸的肽时，会生成一种可通过正交方式进行功能化的酮。这种新策略可以克服核糖体翻译的一个局限性，提供一种将不可翻译基团（如碳水化合物）引入氨基酸侧链的方法，并且将允许核糖体生成糖肽，只需要在待掺入的分子中引入一个游离硫醇即可。结合筛选技术，设想该策略能够发现具有接近天然但水解稳定的硫糖苷键的生物活性糖肽。
