Catalytically active high performance auxiliaries for the proximity-induced native chemical peptide ligation

天然化学连接（NCL）通常用于蛋白质的全化学合成。在该过程中，通过肽硫酯与半胱氨酸肽的化学选择性反应连接未保护的肽片段。当“困难的”肽段由于低溶解度而不反应或仅非常缓慢地反应时，问题出现，使得副反应可能占上风。该项目的目的是使蛋白质的合成，即使“困难”的肽段必须使用。为此，我们将开发功能化的连接助剂。新助剂通过内碱催化作用促进NCL。这将允许反应在任意的、甚至空间位阻的连接位点成功。高反应性连接助剂将简化对更可溶的肽片段的搜索，并且将允许反应在低浓度下发生。此外，助剂和肽硫酯将装备有将反应片段排列成复合物的功能单元。邻近诱导的NCL将在低浓度下成功，这解决了化学蛋白质合成中的主要障碍;未折叠肽段的低溶解度。

Native chemical ligation (NCL) is commonly used in the total chemical synthesis of proteins. In this process, unprotected peptide fragments are ligated by the chemoselective reaction of a peptide thioester with cysteine peptides. Problems arise when "difficult" peptide segments do not react or react only very slowly due to low solubility, so that side reactions can prevail. The aim of this project is to enable the synthesis of proteins even if "difficult" peptide segments have to be used. To this end, we will develop functionalized ligation auxiliaries. The new auxiliaries will accelerate NCL by internal base catalysis. This will allow reactions to succeed at arbitrary, even sterically hindered, ligation sites. Highly reactive ligation auxiliaries will simplify the search for more soluble peptide fragments and will allow reactions to occur despite low concentrations. In addition, the auxiliaries and the peptide thioesters will be armed with functional units that arrange the reacting segments in a complex. Proximity-induced NCL will succeed at low concentrations, which addresses a major obstacle in chemical protein synthesis; the low solubility of unfolded peptide segments.