Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 10, Pages 3025-3028Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.01.062
Keywords
cyclic peptides; enkephalin; conotoxin; lantibiotic; dehydroalanine
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Funding
- NIGMS NIH HHS [R01 GM058822, GM58822, R01 GM058822-08, T32 GM008276] Funding Source: Medline
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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. (c) 2008 Elsevier Ltd. All rights reserved.
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