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- Cyclization (2)
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The idea of privileged scaffolds – that there seem to be more bioactive compounds found around some structures than others – is well established for small drug molecules, but has little significance for standalone peptide secondary structures whose adaptable shapes escape the definition of a 3D motif in the absence of a protein scaffold. Here, we joined two independent biological functions in a single highly restricted peptide to support the hypothesis that the β-hairpin shape is the common basis of two otherwise unrelated biological recognition processes. To achieve this, the hydrophobic cluster HWX4LV from the decapeptide cyclic hairpin model peptide C1-C10 cyclo-CHWEGNKLVC was included in the bicyclic peptide 2. The designed β-hairpin peptide C4-C17, C8-C13 bicyclo-KHQCHWECTZGRCRLVCGRSGS (2, Z = citrulline), serves, on the one hand, as a specific epitope for rheumatoid autoantibodies and, on the other hand, shows a not negligible antibiotic effect against the bacterial strain E. coli AS19.
n this work the synthesis of a linear hexapeptide with a hydroxylamine functionality at the N‐terminus and a ketone instead of the carboxylic acid at the C‐terminus is described. Cyclization by ketoxime formation yields the 19‐membered ring‐expanded cyclic hexapeptide cyclo[Goly‐Val‐Ala‐Pro‐Leu‐Kly] which adopts a main conformer with two intramolecular hydrogen bonds. The hydrolytic stability of a ketoxime lies between the inert amide and the labile imine. The substitution of an amide bond for an iminium bond transforms the irreversible macrocyclization into a reversible process, but macrocyclic imines are difficult to isolate because they are prone to hydrolysis. The enhanced chemical stability of the ketoxime justifies its application in ligation protocols. The detailed NMR analysis of a ketoxime linkage presented here identifies its local conformational preferences in a constrained peptide environment.
Substitution of a peptide bond for an imine transforms the irreversible macrocyclization of peptides into a reversible process. The inherent cyclization tendency of a linear peptide is then analyzable through the equilibrium between the aldehyde and the imine by virtue of the higher reactivity of the corresponding linear peptide aldehyde. The tryptophan side chain of segetalin A aldehyde forms a 12‐membered cyclic indole hemiaminal instead of the 18‐membered macrocyclic imine expected. Herein, we analyzed this uncommon hemiaminal that shows that the biosynthesis of cyclic peptides is not necessarily based on linear precursor peptides with a high inherent macrolactamization tendency.