Premium
Efficient Enzymatic Cyclization of Disulfide‐Rich Peptides by Using Peptide Ligases
Author(s) -
Schmidt Marcel,
Huang YenHua,
Texeira de Oliveira Eduardo F.,
Toplak Ana,
Wijma Hein J.,
Janssen Dick B.,
van Maarseveen Jan H.,
Craik David J.,
Nuijens Timo
Publication year - 2019
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201900033
Subject(s) - peptide , combinatorial chemistry , dna ligase , chemistry , disulfide bond , computational biology , folding (dsp implementation) , chemical ligation , cyclic peptide , enzyme , biochemistry , biology , electrical engineering , engineering
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 θ‐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.