Enzymatic Cyclisation of Peptidomimetics with Incorporated (<i>E</i>)‐Alkene Dipeptide Isosteres

Garbe, Daniel; Sieber, Stephan A.; Bandur, Nina G.; Koert, Ulrich; Marahiel, Mohamed A.

doi:10.1002/cbic.200400042

Cited by 20 publications

(14 citation statements)

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“…Using these substitutions, we specifically targeted the Tyr 1 ‐Gly 2 linkage of Leu‐enkephalin because it is the predominant site of metabolism that is responsible for its short half‐life and limited tissue distribution . Additionally, this site tolerates substitution with E alkenes which suggests that other Tyr 1 ‐Gly 2 substitutions might be tolerated. Therefore, we investigated the synthesis and opioid activity of Tyr 1 ‐ ψ [( Z )CF=CH]‐Gly 2 and Tyr 1 ‐ ψ [( S )/( R )‐CF 3 CH‐NH]‐Gly 2 analogues of enkephalin ( 6 – 8 , Figure ).…”

Section: Figurementioning

confidence: 99%

“…Using these substitutions, we specifically targeted the Tyr 1 -Gly 2 linkageo fL eu-enkephalin because it is the predominant site of metabolism that is responsible for its short half-life and limitedt issue distribution. [26-29, 44, 45] Additionally,t his site tolerates substitution with E alkenes [24,[46][47][48] which suggestst hat other Tyr 1 -Gly 2 substitutions might be tolerated. Therefore, we investigated the synthesis and opioid activity of To test our hypothesis, we first prepared Tyr 1 -y[(Z)CF=CH]-Gly 2 -Gly-Phe-Leu-enkephalin (6)u sing ad iastereoselective Reformatsky-Honda condensation, an E-selective Horner-Wadsworth-Emmons olefination, and aS mI 2 -mediated reduction as key steps (Scheme1A,B).…”

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confidence: 99%

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Synthesis and Opioid Activity of Tyr¹‐ψ[(Z)CF=CH]‐Gly² and Tyr¹‐ψ[(S)/(R)‐CF₃CH‐NH]‐Gly² Leu‐enkephalin Fluorinated Peptidomimetics

et al. 2017

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We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1–ψ[(Z)CF=CH]–Gly2) and trifluoroethylamine (Tyr1–ψ[(S)/(R)-CF3CH–NH]–Gly2) analogues of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exihibited low nanomolar functional activity (5.0 ± 2 nM and 60 ± 15 nM for δ- and μ–opioid receptors, respectively) with a μ/δ-selectivity ratio that mimicked the natural peptide. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position.

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Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

Synthesis and Opioid Activity of Tyr¹‐ψ[(Z)CF=CH]‐Gly² and Tyr¹‐ψ[(S)/(R)‐CF₃CH‐NH]‐Gly² Leu‐enkephalin Fluorinated Peptidomimetics

et al. 2017

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“…Andere Ansätze nutzen SNAc‐Ester von Peptiden mit nicht‐natürlichen Substituenten, z. B. nicht‐natürliche Ester, PEG‐Ketten, Alkine für Click‐Reaktionen, RGD‐Motive und Kohlenhydratmodifizierungen zur Cyclisierung mit Te Tyc oder der Te‐Domäne der Surfactin‐Synthetase (Te Srf ) . Aber auch Te‐Konstrukte von anderen NRPSs wurden für die Cyclisierung von SNAc‐Peptidestern verwendet: das Konstrukt T‐Te Grs mit 2–10‐meren Gramicidin ‐ SNAc‐Estern zur Einstellung verschiedener Ringgrößen, Te/T‐Te CDA der CDA‐Synthetase zur Bewertung von Aminosäurenaustauschen und Acetylierungen sowie T‐Te‐Konstrukte der Synthetasen von A54145 und Daptomycin mit Peptiden zu Aminosäurenaustauschen, zu Veränderungen der Ringgröße und zur Makrolactamisierung (Thr→Dab) .…”

Section: Erzeugung Von Strukturdiversität Durch Nrpssunclassified

Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

Süßmuth

Mainz

2017

Angewandte Chemie

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Nicht‐ribosomale Peptidsynthetasen (NRPSs) sind große Multienzymmaschinerien, die zahlreiche Peptide mit enormer struktureller und funktionaler Diversität erzeugen. Unter diesen Produkten befinden sich mehr als 20 auf dem Markt befindliche Wirkstoffe, darunter Antibiotika (Penicillin, Vancomycin), antitumorale Medikamente (Bleomycin) und Immunsuppressiva (Cyclosporin). In den vergangenen Jahrzehnten haben biochemische sowie strukturbiologische Studien mechanistische Einblicke in die hochkomplexen NRPSs gewährt. Dieser Aufsatz fasst den aktuellen Kenntnisstand über die zugrundeliegenden Mechanismen von NRPSs zusammen und gibt einen Überblick über die Vielfalt ihrer Produkte. Ebenso behandelt werden die Probleme und Herausforderungen, die mit der Umprogrammierung von NRPS‐Systemen einhergehen. Das Potenzial einer solchen Umprogrammierung liegt begründet in einer nachhaltigen Generierung von Wirkstoffanaloga und neuen Substanzbibliotheken, die anderenfalls kaum zugänglich sind.

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“…10) (65), which could be used to further optimize macrocyclic peptide/polyketide natural products, such as the immunosuppressant rapamycin and the anticancer agent epothilone (31). Furthermore, the insertion of (E)-alkene-dipeptide isosters allows the peptide backbone to be modified postsynthetically by chemical metathesis (40).…”

Section: Chemoenzymatic Approaches Toward Novel Cyclopeptidesmentioning

confidence: 99%

Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides

Grünewald

Marahiel

2006

Microbiol Mol Biol Rev

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200

134

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SUMMARY Non-ribosomally synthesized peptides have compelling biological activities ranging from antimicrobial to immunosuppressive and from cytostatic to antitumor. The broad spectrum of applications in modern medicine is reflected in the great structural diversity of these natural products. They contain unique building blocks, such as d-amino acids, fatty acids, sugar moieties, and heterocyclic elements, as well as halogenated, methylated, and formylated residues. In the past decades, significant progress has been made toward the understanding of the biosynthesis of these secondary metabolites by nonribosomal peptide synthetases (NRPSs) and their associated tailoring enzymes. Guided by this knowledge, researchers genetically redesigned the NRPS template to synthesize new peptide products. Moreover, chemoenzymatic strategies were developed to rationally engineer nonribosomal peptides products in order to increase or alter their bioactivities. Specifically, chemical synthesis combined with peptide cyclization mediated by nonribosomal thioesterase domains enabled the synthesis of glycosylated cyclopeptides, inhibitors of integrin receptors, peptide/polyketide hybrids, lipopeptide antibiotics, and streptogramin B antibiotics. In addition to the synthetic potential of these cyclization catalysts, which is the main focus of this review, different enzymes for tailoring of peptide scaffolds as well as the manipulation of carrier proteins with reporter-labeled coenzyme A analogs are discussed.

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Enzymatic Cyclisation of Peptidomimetics with Incorporated (E)‐Alkene Dipeptide Isosteres

Abstract: A key to the development of new antibiotics with increased efficiency can be found in (E)‐alkene dipeptide isosteres. Here we report on the incorporation of such a dipeptide isostere into a linear peptide precursor by chemical synthesis in combination with enzymatic cyclisation.

Cited by 20 publications

References 14 publications

Synthesis and Opioid Activity of Tyr¹‐ψ[(Z)CF=CH]‐Gly² and Tyr¹‐ψ[(S)/(R)‐CF₃CH‐NH]‐Gly² Leu‐enkephalin Fluorinated Peptidomimetics

Synthesis and Opioid Activity of Tyr¹‐ψ[(Z)CF=CH]‐Gly² and Tyr¹‐ψ[(S)/(R)‐CF₃CH‐NH]‐Gly² Leu‐enkephalin Fluorinated Peptidomimetics

Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides

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Enzymatic Cyclisation of Peptidomimetics with Incorporated (E)‐Alkene Dipeptide Isosteres

Abstract: A key to the development of new antibiotics with increased efficiency can be found in (E)‐alkene dipeptide isosteres. Here we report on the incorporation of such a dipeptide isostere into a linear peptide precursor by chemical synthesis in combination with enzymatic cyclisation.

Cited by 20 publications

References 14 publications

Synthesis and Opioid Activity of Tyr1‐ψ[(Z)CF=CH]‐Gly2 and Tyr1‐ψ[(S)/(R)‐CF3CH‐NH]‐Gly2 Leu‐enkephalin Fluorinated Peptidomimetics

Synthesis and Opioid Activity of Tyr1‐ψ[(Z)CF=CH]‐Gly2 and Tyr1‐ψ[(S)/(R)‐CF3CH‐NH]‐Gly2 Leu‐enkephalin Fluorinated Peptidomimetics

Nicht‐ribosomale Peptidsynthese – Prinzipien und Perspektiven

Chemoenzymatic and Template-Directed Synthesis of Bioactive Macrocyclic Peptides

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Product

Resources

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Synthesis and Opioid Activity of Tyr¹‐ψ[(Z)CF=CH]‐Gly² and Tyr¹‐ψ[(S)/(R)‐CF₃CH‐NH]‐Gly² Leu‐enkephalin Fluorinated Peptidomimetics

Synthesis and Opioid Activity of Tyr¹‐ψ[(Z)CF=CH]‐Gly² and Tyr¹‐ψ[(S)/(R)‐CF₃CH‐NH]‐Gly² Leu‐enkephalin Fluorinated Peptidomimetics