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Omniligase‐1: A Powerful Tool for Peptide Head‐to‐Tail Cyclization
Author(s) -
Schmidt Marcel,
Toplak Ana,
Quaedflieg Peter J. L. M.,
Ippel Hans,
Richelle Gaston J. J.,
Hackeng Tilman M.,
van Maarseveen Jan H.,
Nuijens Timo
Publication year - 2017
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201700314
Subject(s) - chemistry , chemical ligation , peptide , oxidative folding , amino acid , combinatorial chemistry , stereochemistry , peptide synthesis , enzyme , organic chemistry , biochemistry , cysteine
Strategies for the efficient synthesis of peptide macrocycles have been a long‐standing goal. In this paper, we demonstrate the use of the peptide ligase termed omniligase‐1 as a versatile and broadly applicable enzymatic tool for peptide cyclization. Several head‐to‐tail (multi)cyclic peptides have been synthesized, including the cyclotide MCoTI‐II. Cyclization and oxidative folding of the cyclotide MCoTI‐II were efficiently performed in a one‐pot reaction on a 1‐gram scale. The native cyclotide was isolated and the correct disulfide bonding pattern was confirmed by NMR structure determination. Furthermore, compatibility of chemo‐enzymatic peptide synthesis (CEPS) using omniligase‐1 with methods such as chemical ligation of peptides onto scaffolds (CLIPS) was successfully demonstrated by synthesizing a kinase‐inhibitor derived tricyclic peptide. Our studies indicate that the minimal ring size for omniligase‐1 mediated cyclization is 11 amino acids, whereas the cyclization of peptides longer than 12 amino acids proceeds with remarkable efficiency. In addition, several macrocycles containing non‐peptidic backbones (e.g., polyethylene glycol), isopeptide bonds (amino acid side‐chain attachment) as well as d ‐amino acids could be efficiently cyclized.