期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 45, 页码 24137-24143出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202107861
关键词
antibiotics; disulfide bonds; palladium; peptide synthesis; stepwise oxidation
资金
- Israel Science Foundation (ISF) [521/19]
- Technion
- Jordan and Irene Tark Academic Chair
This study presents a new approach for synthesizing disulfide-rich bioactive molecules, addressing previous challenges in preparation. Experimental results demonstrate the essential role of the order of disulfide bond formation in proteins with knotted structures. This methodology was utilized to synthesize novel analogues of plectasin with enhanced efficacy against MRSA.
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.
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