Omniligase-1: A Powerful Tool for Peptide Head-to-Tail Cyclization

Marcel Schmidt, Ana Toplak, Peter J. L. M. Quaedflieg, Hans Ippel, Gaston J. J. Richelle, Tilman M. Hackeng, Jan H. van Maarseveen, Timo Nuijens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

44 Citations (Web of Science)

Abstract

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-peptidicbackbones (e.g., polyethylene glycol), isopeptide bonds (amino acid sidechain attachment) as well as d-amino acids could be efficiently cyclized.

Original languageEnglish
Pages (from-to)2050-2055
Number of pages6
JournalAdvanced Synthesis & Catalysis
Volume359
Issue number12
DOIs
Publication statusPublished - 19 Jun 2017

Keywords

  • chemo-enzymatic peptide synthesis (CEPS)
  • cyclic peptides
  • cyclization
  • cyclotide synthesis
  • cyclotides
  • enzyme catalysis
  • head-to-tail cyclization
  • ligases
  • macrocycles
  • omniligase-1
  • peptides
  • SQUASH TRYPSIN-INHIBITOR
  • CYSTINE KNOT PROTEINS
  • MOMORDICA-COCHINCHINENSIS
  • SEGMENT CONDENSATION
  • CIRCULAR PROTEINS
  • MCOTI-II
  • BACKBONE
  • CYCLOTIDES
  • LIGASE
  • MACROCYCLIZATION

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