Use of lantibiotic synthetases for the preparation of bioactive constrained peptides

Matthew R. Levengood, Wilfred A. van der Donk

Research output: Contribution to journalArticlepeer-review

Abstract

Stabilization of biologically active peptides is a major goal in peptide-based drug design. Cyclization is an often-used strategy to enhance resistance of peptides toward protease degradation and simultaneously improve their affinity for targets by restricting their conformational flexibility. Among the various cyclization strategies, the use of thioether crosslinks has been successful for various peptides including enkephalin. The synthesis of these thioethers can be arduous, especially for longer peptides. Described herein is an enzymatic strategy taking advantage of the lantibiotic synthetase LctM that dehydrates Ser and Thr residues to the corresponding dehydroalanine and dehydrobutyrine residues and catalyzes the Michael-type addition of Cys residues to form thioether crosslinks. The use of LctM to prepare thioether containing analogs of enkephalin, contryphan, and inhibitors of human tripeptidyl peptidase II and spider venom epimerase is demonstrated.

Original languageEnglish (US)
Pages (from-to)3025-3028
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number10
DOIs
StatePublished - May 15 2008

Keywords

  • Conotoxin
  • Cyclic peptides
  • Dehydroalanine
  • Enkephalin
  • Lantibiotic

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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