通过四嗪硫醇交换实现快速、无痕迹和简单的肽环化。

IF 1.8 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Daniëlle W. T. Geers, Katerina Gavriel, Kevin Neumann
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引用次数: 0

摘要

与线性肽相比,环肽具有许多优点,包括在生物环境中延长稳定性和增强结合亲和力。通常,通过分别广泛使用正交保护基或化学选择性连接策略,在树脂或溶液中形成酰胺键,使肽环化。在这里,我们表明化学选择性的四嗪硫醇交换是一种强大的工具,可以快速原位环化肽,而不需要额外的活化试剂或广泛的保护基重组。在弱酸性环境(pH 6.5)并且具有无痕的性质。可使用标准固相肽合成方案将快速获得的不对称硫化物四嗪构建块掺入树脂上,并与三氟乙酸裂解条件正交。即使与大量过量的游离硫醇一起孵育,环化肽也显示出高稳定性。由于其无痕迹和温和的性质,我们预计四嗪硫醇交换将对原位形成环肽库具有很高的价值,从而适用于药物的发现和开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Rapid, traceless and facile peptide cyclization enabled by tetrazine-thiol exchange

Rapid, traceless and facile peptide cyclization enabled by tetrazine-thiol exchange

Rapid, traceless and facile peptide cyclization enabled by tetrazine-thiol exchange

Cyclic peptides offer many advantages compared to their linear counterparts, including prolonged stability within the biological environment and enhanced binding affinity. Typically, peptides are cyclized by forming an amide bond, either on-resin or in solution, through extensive use of orthogonal protecting groups or chemoselective ligation strategies, respectively. Here, we show that the chemoselective tetrazine-thiol exchange is a powerful tool for rapid in situ cyclization of peptides without the need for additional activation reagents or extensive protecting group reshuffling. The reaction between N-terminal sulfide-bearing unsymmetric tetrazines and internal cysteines occurs spontaneously within a mildly acidic environment (pH 6.5) and is of traceless nature. The rapidly available unsymmetric sulfide tetrazine building blocks can be incorporated on resin using standard solid-phase peptide synthesis protocols and are orthogonal to trifluoroacetic acid cleavage conditions. The cyclized peptides display high stability, even when incubated with a large excess of free thiols. Due to its traceless and mild nature, we expect that the tetrazine-thiol exchange will be of high value for the in situ formation of cyclic peptide libraries, thus being applicable in drug discovery and development.

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来源期刊
Journal of Peptide Science
Journal of Peptide Science 生物-分析化学
CiteScore
3.40
自引率
4.80%
发文量
83
审稿时长
1.7 months
期刊介绍: The official Journal of the European Peptide Society EPS The Journal of Peptide Science is a cooperative venture of John Wiley & Sons, Ltd and the European Peptide Society, undertaken for the advancement of international peptide science by the publication of original research results and reviews. The Journal of Peptide Science publishes three types of articles: Research Articles, Rapid Communications and Reviews. The scope of the Journal embraces the whole range of peptide chemistry and biology: the isolation, characterisation, synthesis properties (chemical, physical, conformational, pharmacological, endocrine and immunological) and applications of natural peptides; studies of their analogues, including peptidomimetics; peptide antibiotics and other peptide-derived complex natural products; peptide and peptide-related drug design and development; peptide materials and nanomaterials science; combinatorial peptide research; the chemical synthesis of proteins; and methodological advances in all these areas. The spectrum of interests is well illustrated by the published proceedings of the regular international Symposia of the European, American, Japanese, Australian, Chinese and Indian Peptide Societies.
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