Triazole-Based Mimicking of the Disulfide Bond Motif in Cyclic Peptides

• Applicant: Dr. Kai Holland-Nell
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2008 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 76551338

The chemical synthesis of macrocycles is one basic challenge in peptidic drug design. Thereby, disulfide bond formation represents a principle reaction to obtain correctly fold and biologically active peptides. The key aspect of this application, however, focuses on mimicking the essential disulfide bond motif. The replacement of disulfide units by triazoles is a novel approach in order to synthesize cyclic peptides. The introduction of the Cu(I)-catalyzed Huisgen cycloaddition (click chemistry) provides an excellent tool to produces macrocycles under triazole formation. By using azido and propargyl building blocks the cyclization occurs virtually quantitive with high regio and stereo-selectivity. As a result of the orthogonality of this reaction protecting groups are generally dispensable. The benefits of click chemistry will be used to mimic more complex disulfide patterns, which are difficult to synthesize by conventional methods. Two model peptides of significant biological relevance are chosen in order to validate this strategy. Synthesis, structural analysis and biological characterization of those peptides will be performed in order to evaluate the potential of click chemistry in peptide macrocycle formation.

• DFG Programme: Research Fellowships
• International Connection: Denmark
• Host: Professor Morten Meldal