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

• Applicant: Professor Dr. Oliver Seitz
• Subject Area: Biological and Biomimetic Chemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524247156

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.

• DFG Programme: Research Grants