Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics

Emilia Oueis, Marcel Jaspars, Nicholas J. Westwood, James H. Naismith

Research output: Contribution to journalArticle

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Abstract

The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme-mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4-substituted 1,2,3-triazole moieties. The introduction of non-peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non-natural triazole-containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.

Original languageEnglish
Pages (from-to)5842-5845
Number of pages4
JournalAngewandte Chemie International Edition
Volume55
Issue number19
Early online date5 Apr 2016
DOIs
Publication statusPublished - 4 May 2016

Fingerprint

Triazoles
Peptides
Enzymes
Cyclic Peptides
Substrates
Bioactivity
Scaffolds
Tuning
Physical properties
Proteins
Molecules

Keywords

  • biotransformation
  • cyanobactin
  • cyclic peptides
  • peptidomimetics
  • triazole

Cite this

Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics. / Oueis, Emilia; Jaspars, Marcel; Westwood, Nicholas J.; Naismith, James H.

In: Angewandte Chemie International Edition, Vol. 55, No. 19, 04.05.2016, p. 5842-5845.

Research output: Contribution to journalArticle

Oueis, Emilia ; Jaspars, Marcel ; Westwood, Nicholas J. ; Naismith, James H. / Enzymatic Macrocyclization of 1,2,3-Triazole Peptide Mimetics. In: Angewandte Chemie International Edition. 2016 ; Vol. 55, No. 19. pp. 5842-5845.
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AB - The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme-mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4-substituted 1,2,3-triazole moieties. The introduction of non-peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non-natural triazole-containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.

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