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• W153591018 abstract "Disulfide bonds play a decisive role in the folding and stability in most classes of extra-cellular bioactive peptides including hormones, neurotransmitters, growth factors, enzyme inhibitors, antimicrobial peptides and venom toxins. Controlling the folding of disulfide-rich peptides is not trivial and often determines the rate and the success of their synthesis. This work introduces an alternative strategy to direct disulfide formation by substituting cysteine by the nearly isosteric selenocysteine. It describes a novel methodology that allows efficient access to conopeptide libraries via an on-resin oxidation approach and furthermore analyzes disulfide bridge mimetics of increased stability of oxytocin, involving new synthetic routes and revealing an interesting functional selectivity switch for the human oxytocin receptor. Chapter 1 & 2 serve as an overall introduction with the main focus on the chemical aspects of the 21st proteinogenic amino acid selenocysteine in peptides and proteins. It describes the physicochemical properties of selenium/sulfur and selenocysteine/cysteine based on comprehensive structural (X-ray, NMR, CD) and biological data, and illustrates why selenocysteine is considered the most conservative substitution for cysteine. The synthetic methods on selenocysteine incorporation into peptides and proteins were reviewed, including an overview of the selenocysteine building block syntheses for Boc- and Fmoc- solid phase peptide synthesis. Selenocysteine-mediated reactions are addressed such as native chemical ligation and dehydroalanine formation towards peptide conjugation. Selenopeptides have very interesting and distinct properties, which led to a diverse range of applications such as structural, functional and mechanistic probes, robust scaffolds, enzyme engineering, peptide conjugation and folding tools, all discussed in this review. Chapter 3 contains the core work of the thesis and describes how selenocysteine was used to control regioselective folding of an important class of disulfide -rich peptides, the α−conotoxins. Driven by the physicochemical differences of cysteine and selenocysteine such as lower pKa, lower redox potential and higher nucleophilicity, it was possible to direct the peptides into desired folds by replacing pairs of cysteine residues with isosteric selenocysteine residues. Selective access to the globular and ribbon isoforms of α-AuIB, α-MI, α-[A10L]-PnIA, α-RgIA and α-ImI was achieved through oxidative folding in situ in less than ten minutes. CD and NMR analysis confirmed the isosteric character of the α-selenoconotoxins and comparison of the crystal structures of α-PnIA and Sec[2,4]-[A10L]-PnIA (1.4 A) showed an increase of bond length of only 0.3 A and Se-Se torsion angles within 4-6o of the corresponding Cys analogue. The α-selenoconotoxins exhibited comparable or more potent inhibition of acetylcholine-evoked currents mediated by nAChR subtypes (α3β2, α7, α1β1δγ) expressed in Xenopus oocytes and on rat hemi-diaphragm contraction assays. Studies in rat plasma and in equimolar glutathione solutions showed increased stability to scrambling of the selenocysteine isoforms. Chapter 4 describes the development of resin-supported chemistry using Boc-SPPS that leads directly to correctly folded α-conotoxins on resin. Drug lead optimization, high-throughput screening and structure-activity relationship studies often require easy synthetic access to a large number of analogues. This has been hampered by tedious and time-consuming folding and purification processes. The use of a safety-catch acid labile linker on a water compatible, amphiphilic polyethyleneglycol support (ChemMatrix) allows side-chain deprotection and subsequent oxidation on-resin in aqueous phosphate buffer solution at pH 8.4. A selection of small to medium sized peptides, including the α-conotoxins MI, Vc1.1 and PnIA, were synthesized and oxidized on resin. The solid support had an effect on the isomer formation of α-MI and α-Vc1.1, yielding all three possible isomers. Control over the isomer formation in Sec[3,8]-MI was obtained by replacing a pair of cysteine residues with a pair of isosteric selenocysteine residues, showing that seleno-chemistry is compatible with on-resin chemistry. Peptide cleavage was achieved by reductive acidolysis and peptides were obtained in >90% purity either by individual cleavage and RP-HPLC purification using labeled solvent-permeable resin bags, or by an efficient ‘one-pot’ cleavage and RP-HPLC-purification step. Chapter 5 investigates structure-activity relationships of more stable disulfide bond mimetics of oxytocin (lanthionine, cystathionine and selenium analogues) for the human oxytocin and vasopressin V1a receptor. A new on-resin thioether formation and two novel selenocysteine building blocks (Nα−tert-butyloxycarbonyl-acetamidomethyl-L-seleno-cysteine (Boc-L-Sec(Acm)-OH) and Nα−tert-butyloxycarbonyl-4-nitrobenzyl-L-selenocysteine (Boc-L-Sec(pNB)-OH)) were developed for analogue synthesis. The cystathionine and selenylsulfur analogues retained full binding and functional activity, while the lanthionine analogues surprisingly abolished activity. Metabolic stability in rat and human plasma was improved over oxytocin (12h) in the selenium analogues (20-25h), and in the all-D-, N-to C-terminal-cyclized- and all-D-retroinverse-oxytocin (> 48h). Substitution of the C-terminal carboxylic amide to a carboxylic acid in the selenium analogue [C1,6U]-Oxytocin-OH revealed an interesting 2600-fold functional selectivity switch for the human oxytocin receptor. The chemistry introduced in this study facilitates access to analogues with enhanced metabolic stability that retained full activity and has the potential to be applied to other important classes of disulfide-rich peptides." @default.
• W153591018 created "2016-06-24" @default.
• W153591018 creator A5050804038 @default.
• W153591018 date "2009-05-25" @default.
• W153591018 modified "2023-09-27" @default.
• W153591018 title "Peptide engineering - controlling the folding of disulfide-rich peptides" @default.
• W153591018 hasPublicationYear "2009" @default.
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