Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics

• Published in: Angewandte Chemie International Edition Vol. 55; no. 19; pp. 5842 - 5845
• Main Authors: Oueis, Emilia, Jaspars, Marcel, Westwood, Nicholas J., Naismith, James H.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 04.05.2016; Wiley; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Amino Acid Sequence; biotransformation; Chemistry; Chemistry, Multidisciplinary; Communication; Communications; cyanobactin; cyclic peptides; Cyclization; Enzymes; Peptide Hydrolases - metabolism; Peptides; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; peptidomimetics; Physical Sciences; Science & Technology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; triazole; Triazoles - chemistry; cyclic peptides; biotransformation; DRUG DISCOVERY; CHEMISTRY; cyanobactin; peptidomimetics; CYCLIZATION; triazole
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201601564

The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme‐mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4‐substituted 1,2,3‐triazole moieties. The introduction of non‐peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non‐natural triazole‐containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation. The macrocyclase enzyme PatGmac from the patellamide pathway of the cyanobactin family successfully macrocyclized non‐natural peptides where one, two, or three 1,4‐substituted 1,2,3‐triazole rings were incorporated at different positions of the core peptide. 19 cyclic peptides were macrocyclized by PatGmac, among which 9 were isolated and fully characterized.