title: Use of lantibiotic synthetases for the preparation of bioactive constrained peptides.
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.
authors.affiliation: Department of Chemistry, University of Illinois, 600 S. Mathews Avenue, Urbana, IL 61801, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Levengood
authors.forename: Wilfred A
authors.initials: WA
authors.lastname: van der Donk
mesh_terms: D000626:Aminopeptidases; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry; D001430:Bacteriocins / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D015195:Drug Design; D004745:Enkephalins / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry / Q000187:drug effects; D013111:Spider Venoms / Q000737:chemistry; D013237:Stereoisomerism; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D004745:Enkephalins; D004791:Enzyme Inhibitors; D004798:Enzymes; C481644:LctM protein, Lactococcus lactis; D010455:Peptides; D010456:Peptides, Cyclic; D013111:Spider Venoms; D013440:Sulfides; C102355:contryphan; C082508:lacticin 481; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D019998:Racemases and Epimerases