Insight on the Order of Regioselective Ultrafast Formation of Disulfide Bonds in (Antimicrobial) Peptides and Miniproteins. Issue 45 (7th October 2021)

• Record Type: Journal Article
• Authors: Laps, Shay; Atamleh, Fatima; Kamnesky, Guy; Uzi, Shaked; Meijler, Michael M.; Brik, Ashraf
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 45(2021)
• Page Start: 24137
• Page End: 24143
• Publication Date: 2021-10-07
• Subjects: antibiotics -- disulfide bonds -- palladium -- peptide synthesis -- stepwise oxidation; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202107861
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Disulfide‐rich peptides and proteins are among the most fascinating bioactive molecules. The difficulties associated with the preparation of these targets have prompted the development of various chemical strategies. Nevertheless, the production of these targets remains very challenging or elusive. Recently, we introduced a strategy for one‐pot disulfide bond formation, tackling most of the previous limitations. However, the effect of the order of oxidation remained an underexplored issue. Herein we report on the complete synthetic flexibility of the approach with respect to the order of oxidation of three disulfide bonds in targets that lack the knot motif. In contrast, our study reveals an essential order of disulfide bond formation in the EETI‐II knotted miniprotein. This synthetic strategy was applied for the synthesis of novel analogues of the plectasin antimicrobial peptide with enhanced activities against methicillin‐resistant Staphylococcus aureus (MRSA), a notorious human pathogen. Abstract : Chemoselective palladium catalysis used for the regioselective ultrafast synthesis of peptides and proteins bearing multiple disulfide bonds provided important insight into the order of oxidation (see picture). The approach, which produced a novel antimicrobial plectasin derivative with enhanced antibiotic activity relative to that of the natural product, should enable the practical synthesis of peptide/protein libraries for various applications.