Journal
CHEMBIOCHEM
Volume 20, Issue 12, Pages 1524-1529Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201900033
Keywords
chemoenzymatic peptide synthesis (CEPS); cyclotides; enzyme catalysis; macrocycles; omniligase-1
Funding
- Australian Research Council Laureate Fellowship [FL150100146]
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Disulfide-rich macrocyclic peptides-cyclotides, for example-represent a promising class of molecules with potential therapeutic use. Despite their potential their efficient synthesis at large scale still represents a major challenge. Here we report new chemoenzymatic strategies using peptide ligase variants-inter alia, omniligase-1-for the efficient and scalable one-pot cyclization and folding of the native cyclotides MCoTI-II, kalata B1 and variants thereof, as well as of the theta-defensin RTD-1. The synthesis of the kB1 variant T20K was successfully demonstrated at multi-gram scale. The existence of several ligation sites for each macrocycle makes this approach highly flexible and facilitates both the larger-scale manufacture and the engineering of bioactive, grafted cyclotide variants, therefore clearly offering a valuable and powerful extension of the existing toolbox of enzymes for peptide head-to-tail cyclization.
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