Synthesis and Biological Activities of Cyclic Lanthionine Enkephalin Analogues:  <i>δ</i>-Opioid Receptor Selective Ligands

Rew, Yosup; Malkmus, Shelle; Svensson, Camilla I.; Yaksh, Tony L.; Chung, Nga N.; Schiller, Peter W.; Cassel, Joel; DeHaven, Robert N.; Taulane, Joseph P.; Goodman, Murray

doi:10.1021/jm020108k

Cited by 94 publications

(68 citation statements)

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“…A des-Gly analog of DPDPE, H-Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13), also turned out to be a potent and selective DOPr agonist . Among various prepared cyclic lanthionine enkephalin analogs, H-Tyr-c[D-Val L -Gly-Phe-D-Ala L ]OH displayed high DOPr agonist potency and selectivity (Rew et al, 2002) and was shown to attenuate cancerrelated bone pain with systemic administration (BraininMattos et al, 2006). Structural modifications of the already potent and very selective deltorphins resulted in compounds with further improved DOPr binding affinity and selectivity (Sasaki et al, 1991;Sasaki and Chiba, 1995;Bryant et al, 1997).…”

Section: D-opioid Receptor Ligandsmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

et al. 2016

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Section: D-opioid Receptor Ligandsmentioning

confidence: 99%

Molecular Pharmacology ofδ-Opioid Receptors

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“…2 A notable example features the stabilization of enkephalin by the introduction of a thioether crosslink between two alanines (Figure 1), which increased the bioactivity of the compound by several orders of magnitude due to increased biostability. 3 Other studies have also shown the increased stability of peptides and proteins by thioether crosslinks. 4,5 Thioether crosslinks between two alanine residues are called lanthionines and their synthesis has received much attention.…”

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confidence: 98%

Use of lantibiotic synthetases for the preparation of bioactive constrained peptides

Levengood

Donk

2008

Bioorganic & Medicinal Chemistry Letters

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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 towards protease degradation and simultaneously improve their affinity for targets by restricting their conformational flexibility. Amongst 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.Interest in peptide-based materials for use in human therapeutics has greatly increased in recent years, and fully synthetic peptide drugs have increasingly reached the clinic. 1 The proteolytic instability of peptides still presents a limitation, however, for widespread utilization of peptide therapeutics. An often employed strategy for the design of peptide-based drugs with improved selectivity and decreased proteolytic susceptibility involves cyclization to constrain their conformational flexibility. 2 A notable example features the stabilization of enkephalin by the introduction of a thioether crosslink between two alanines (Figure 1), which increased the bioactivity of the compound by several orders of magnitude due to increased biostability. 3 Other studies have also shown the increased stability of peptides and proteins by thioether crosslinks. 4,5 Thioether crosslinks between two alanine residues are called lanthionines and their synthesis has received much attention. 6 Despite important recent advances, 7-12 at present it is still difficult to introduce these structures efficiently into synthetic peptides, especially for large peptides. One promising route to these structures is through the biosynthetic machinery for lantibiotics. These compounds are ribosomally synthesized and posttranslationally modified antimicrobial peptides. 13,14 The first step in the modification process of class II lantibiotics involves phosphorylation of Ser and Thr residues and subsequent elimination of the phosphate group to generate dehydroalanines and Z-dehydrobutyrines, respectively ( Figure 2). 15 In a succeeding step, intramolecular Michael-type addition by Cys residues to the dehydroamino acids forms the lanthionine (from Ser) and methyllanthionine (from Thr) crosslinks. Lacticin 481 synthetase (LctM) carries out both steps in a regio-and Correspondence to: Wilfred A. van der Donk. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of ...

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“…Intramolecular thioether bridge formation especially is an effective way to protect peptides against proteolytic degradation. Introduction of thioether bridges in peptides has been effectively applied on peptides like somatostatin, enkephalin, and an epitope of the herpes simplex virus glycoprotein D. For all these peptides, an increased catabolic stability was observed compared with their linear counterparts (Rew et al, 2002;Tugyi et al, 2005). Thioether bridges are more stable than peptide bonds and disulfide bridges (Tugyi et al, 2005).…”

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confidence: 99%