Chemical Synthesis and Cell-Free Expression of Thiazoline Ring-Bridged Cyclic Peptides and Their Properties on Biomembrane Permeability

Abstract Cyclic peptides that exhibit biomembrane permeability provide a useful platform in the development of peptide drugs. Here, the reaction characteristics and versatility of a novel type of cyclic peptide having a thiazoline ring structure in the main chain were investigated. The thiazoline ring-bridged cyclic peptides were chemically synthesized by the intramolecular cyclization of linear peptides composed of N-terminal Cys and a non-natural amino acid having a cyano group on the side chain. The thiazoline ring-bridged cyclic peptides had higher model membrane permeability than amide- and thioether-bridged cyclic peptides with similar amino acid sequences. By comparing the solution structures, the factors that contribute to the higher membrane permeability were examined. In addition, the present peptide cyclization was applied to a cell-free translation system. The expression of peptides having the cyanated non-natural amino acids and subsequent spontaneous cyclization were successfully achieved.