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1.
Qian Qu Shuai Gao Fangming Wu Meng-Ge Zhang Ying Li Long-Hua Zhang Dr. Donald Bierer Prof. Chang-Lin Tian Prof. Ji-Shen Zheng Prof. Dr. Lei Liu 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(15):6093-6101
The use of synthetic bridges as surrogates for disulfide bonds has emerged as a practical strategy to obviate the poor stability of some disulfide-containing peptides. However, peptides incorporating large-span synthetic bridges are still beyond the reach of existing methods. Herein, we report a native chemical ligation (NCL)-assisted diaminodiacid (DADA) strategy that enables the robust generation of disulfide surrogate peptides incorporating surrogate bridges up to 50 amino acids in length. This strategy provides access to some highly desirable but otherwise impossible-to-obtain disulfide surrogates of bioactive peptide. The bioactivities and structures of the synthetic disulfide surrogates were verified by voltage clamp assays, NMR, and X-ray crystallography; and stability studies established that the disulfide replacements effectively overcame the problems of disulfide reduction and scrambling that often plague these pharmacologically important peptides. 相似文献
2.
Disulfide bond‐containing peptides are useful molecular scaffolds with diagnostic and therapeutic applications due to their good biological activity and good target selectivity, but their utility is sometimes limited by the lability of the disulfide moiety under reducing conditions and in the presence of disulfide bond isomerase. The development of disulfide surrogates with improved redox stability has been an area of ongoing research; and one possible strategy is based on a diaminodiacid (DADA) moiety, which can be used to synthesize the disulfide bond replacement peptides with precise structures and enhanced stability through automated solid‐phase peptide synthesis (SPPS). This review summarizes recent developments in the DADA‐based SPPS of peptide disulfide surrogates. Some representative applications and structural studies on the DADA‐based disulfide surrogates are described. 相似文献
3.
Fangzhou Wu Dr. John P. Mayer Dr. Alexander N. Zaykov Dr. Fa Zhang Dr. Fa Liu Prof. Richard D. DiMarchi 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(28):9777-9783
Human insulin‐like peptide‐6 (INSL‐6) belongs to the insulin superfamily and shares the distinctive disulfide bond configuration of human insulin. In this report we present the first chemical synthesis of INSL‐6 utilizing fluorenylmethyloxycarbonyl‐based (Fmoc) solid‐phase peptide chemistry and regioselective disulfide bond construction protocols. Due to the presence of an oxidation‐sensitive tryptophan residue, two new orthogonal synthetic methodologies were developed. The first method involved the identification of an additive to suppress the oxidation of tryptophan during iodine‐mediated S‐acetamidomethyl (Acm) deprotection and the second utilized iodine‐free, sulfoxide‐directed disulfide bond formation. The methodologies presented here offer an efficient synthetic route to INSL‐6 and will further improve synthetic access to other multiple‐disulfide‐containing peptides with oxidation‐sensitive residues. 相似文献
4.
Andrew M. White Simon J. de Veer Guojie Wu Peta J. Harvey Kuok Yap Gordon J. King Joakim E. Swedberg Conan K. Wang Ruby H. P. Law Thomas Durek David J. Craik 《Angewandte Chemie (International ed. in English)》2020,59(28):11273-11277
Ruthenium‐catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5‐disubstituted 1,2,3‐triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross‐linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor‐1. NMR and X‐ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole‐bridged peptides also displayed superior half‐lives in liver S9 stability assays compared to disulfide‐bridged peptides. This work establishes a foundation for the application of 1,5‐disubstituted 1,2,3‐triazoles as disulfide mimetics. 相似文献
5.
A One‐Pot Chemically Cleavable Bis‐Linker Tether Strategy for the Synthesis of Heterodimeric Peptides
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Nitin A. Patil Dr. Julien Tailhades Dr. John A. Karas Prof. Frances Separovic Prof. John D. Wade Dr. Mohammed Akhter Hossain 《Angewandte Chemie (International ed. in English)》2016,55(47):14552-14556
Heterodimeric peptides linked by disulfide bonds are attractive drug targets. However, their chemical assembly can be tedious, time‐consuming, and low yielding. Inspired by the cellular synthesis of pro‐insulin in which the two constituent peptide chains are expressed as a single‐chain precursor separated by a connecting C‐peptide, we have developed a novel chemically cleavable bis‐linker tether which allows the convenient assembly of two peptide chains as a single “pro”‐peptide on the same solid support. Following the peptide cleavage and post‐synthetic modifications, this bis‐linker tether can be removed in one‐step by chemical means. This method was used to synthesize a drug delivery‐cargo conjugate, TAT‐PKCi peptide, and a two‐disulfide bridged heterodimeric peptide, thionin (7‐19)‐(24‐32R), a thionin analogue. To our knowledge, this is the first report of a one‐pot chemically cleavable bis‐linker strategy for the facile synthesis of cross‐bridged two‐chain peptides. 相似文献
6.
Synthesis of Sulfotyrosine‐Containing Peptides by Incorporating Fluorosulfated Tyrosine Using an Fmoc‐Based Solid‐Phase Strategy
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Wentao Chen Dr. Jiajia Dong Dr. Suhua Li Dr. Yu Liu Dr. Yujia Wang Leonard Yoon Dr. Peng Wu Dr. K. Barry Sharpless Dr. Jeffery W. Kelly 《Angewandte Chemie (International ed. in English)》2016,55(5):1835-1838
Tyrosine O‐sulfation is a common protein post‐translational modification that regulates many biological processes, including leukocyte adhesion and chemotaxis. Many peptides with therapeutic potential contain one or more sulfotyrosine residues. We report a one‐step synthesis for Fmoc‐fluorosulfated tyrosine. An efficient Fmoc‐based solid‐phase peptide synthetic strategy is then introduced for incorporating the fluorosulfated tyrosine residue into peptides of interest. Standard simultaneous peptide‐resin cleavage and removal of the acid‐labile side‐chain protecting groups affords the crude peptides containing fluorosulfated tyrosine. Basic ethylene glycol, serving both as solvent and reactant, transforms the fluorosulfated tyrosine peptides into sulfotyrosine peptides in high yield. 相似文献
7.
Racemic and Quasi‐Racemic X‐ray Structures of Cyclic Disulfide‐Rich Peptide Drug Scaffolds
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Conan K. Wang Gordon J. King Susan E. Northfield Paola G. Ojeda Prof. Dr. David J. Craik 《Angewandte Chemie (International ed. in English)》2014,53(42):11236-11241
Cyclic disulfide‐rich peptides have exceptional stability and are promising frameworks for drug design. We were interested in obtaining X‐ray structures of these peptides to assist in drug design applications, but disulfide‐rich peptides can be notoriously difficult to crystallize. To overcome this limitation, we chemically synthesized the L ‐ and D ‐forms of three prototypic cyclic disulfide‐rich peptides: SFTI‐1 (14‐mer with one disulfide bond), cVc1.1 (22‐mer with two disulfide bonds), and kB1 (29‐mer with three disulfide bonds) for racemic crystallization studies. Facile crystal formation occurred from a racemic mixture of each peptide, giving structures solved at resolutions from 1.25 Å to 1.9 Å. Additionally, we obtained the quasi‐racemic structures of two mutants of kB1, [G6A]kB1, and [V25A]kB1, which were solved at a resolution of 1.25 Å and 2.3 Å, respectively. The racemic crystallography approach appears to have broad utility in the structural biology of cyclic peptides. 相似文献
8.
Total Synthesis of Human Hepcidin through Regioselective Disulfide‐Bond Formation by using the Safety‐Catch Cysteine Protecting Group 4,4′‐Dimethylsulfinylbenzhydryl
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Zoltan Dekan Dr. Mehdi Mobli Dr. Michael W. Pennington Dr. Eileen Fung Dr. Elizabeta Nemeth Prof. Paul F. Alewood 《Angewandte Chemie (International ed. in English)》2014,53(11):2931-2934
A safety‐catch cysteine protecting group, S‐4,4′‐dimethylsulfinylbenzhydryl (Msbh), was designed and developed to expand the capabilities of synthetic strategies for the regioselective formation of disulfide bonds in cysteine‐rich peptides. The directed regioselective synthesis of human hepcidin, which contains four disulfide bonds, was undertaken and led to a high‐resolution NMR structure under more physiologically relevant conditions than previously. Conversely, hepcidin synthesized with the formerly assigned vicinal disulfide‐bond connectivity displayed significant conformational heterogeneity under similar conditions. The two synthetic forms of human hepcidin induced ferroportin internalization with apparent EC50 values of 2.0 (native fold, 1 ) and 4.4 nM (non‐native fold, 2 ), with 2 undergoing isomerization to 1 in the presence of ferroportin expressing cells. 相似文献
9.
Intracellular Delivery of Peptidyl Ligands by Reversible Cyclization: Discovery of a PDZ Domain Inhibitor that Rescues CFTR Activity
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Dr. Ziqing Qian Dr. Xiaohua Xu Dr. Jeanine F. Amacher Prof. Dr. Dean R. Madden Prof. Dr. Estelle Cormet‐Boyaka Prof. Dr. Dehua Pei 《Angewandte Chemie (International ed. in English)》2015,54(20):5874-5878
A general strategy was developed for the intracellular delivery of linear peptidyl ligands through fusion to a cell‐penetrating peptide and cyclization of the fusion peptides via a disulfide bond. The resulting cyclic peptides are cell permeable and have improved proteolytic stability. Once inside the cell, the disulfide bond is reduced to produce linear biologically active peptides. This strategy was applied to generate a cell‐permeable peptide substrate for real‐time detection of intracellular caspase activities during apoptosis and an inhibitor for the CFTR‐associated ligand (CAL) PDZ domain as a potential treatment for cystic fibrosis. 相似文献
10.
Dr. Michèle Cristau Dr. Muriel Amblard Dr. Sonia Cantel Prof. Christine Enjalbal Dr. Karine Puget Prof. Jean Martinez Dr. Gilles Subra 《化学:亚洲杂志》2011,6(9):2382-2389
The synthesis and use of novel polymer‐supported reagents for disulfide bond formation is described. This family of supported reagents consists of a series of oxidized methionines grafted onto a solid support. Their cost and the simplicity of their preparation through N‐carboxyanhydride polymerization on beads make them reactants of choice for the formation of disulfide bridges in peptides. 相似文献
11.
Dr. Nitin A. Patil Dr. John A. Karas Prof. Dr. John D. Wade Dr. Mohammed Akhter Hossain Dr. Julien Tailhades 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(36):8599-8603
Structure–activity relationship studies are a highly time-consuming aspect of peptide-based drug development, particularly in the assembly of disulfide-rich peptides, which often requires multiple synthetic steps and purifications. Therefore, it is vital to develop rapid and efficient chemical methods to readily access the desired peptides. We have developed a photolysis-mediated “one-pot” strategy for regioselective disulfide bond formation. The new pairing system utilises two ortho-nitroveratryl protected cysteines to generate two disulfide bridges in less than one hour in good yield. This strategy was applied to the synthesis of complex disulfide-rich peptides such as Rho-conotoxin ρ-TIA and native human insulin. 相似文献
12.
Plant Antimicrobial Peptides Snakin‐1 and Snakin‐2: Chemical Synthesis and Insights into the Disulfide Connectivity
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Dr. Paul W. R. Harris Dr. Sung‐Hyun Yang Prof. Antonio Molina Gemma López Martin Middleditch Prof. Margaret A. Brimble 《Chemistry (Weinheim an der Bergstrasse, Germany)》2014,20(17):5102-5110
Antimicrobial peptides and proteins represent an important class of plant defensive compounds against pathogens and provide a rich source of lead compounds in the field of drug discovery. We describe the effective preparation of the cysteine‐rich snakin‐1 and ‐2 antimicrobial peptides by using a combination of solid‐phase synthesis and native chemical ligation. A subsequent cysteine/cystine mediated oxidative folding to form the six internal disulfide bonds concurrently gave the folded proteins in 40–50 % yield. By comparative evaluation of mass spectrometry, HPLC, biological data and trypsin digest mapping of folded synthetic snakin‐2 compared to natural snakin‐2, we demonstrated that synthetic snakin‐2 possesses full antifungal activity and displayed similar chromatographic behaviour to natural snakin‐2. Trypsin digest analysis allowed tentative assignment of three of the purported six disulfide bonds. 相似文献
13.
Prof. Margaret A. Brimble Dr. Pat J. Edwards Dr. Paul W. R. Harris Dr. Gillian E. Norris Dr. Mark L. Patchett Tom H. Wright Dr. Sung‐Hyun Yang Dr. Sarah E. Carley 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(9):3556-3561
The first total synthesis of glycocin F, a uniquely diglycosylated antimicrobial peptide bearing a rare S‐linked N‐acetylglucosamine (GlcNAc) moiety in addition to an O‐linked GlcNAc, has been accomplished using a native chemical ligation strategy. The synthetic and naturally occurring peptides were compared by HPLC, mass spectrometry, NMR and CD spectroscopy, and their stability towards chymotrypsin digestion and antimicrobial activity were measured. This is the first comprehensive structural and functional comparison of a naturally occurring glycocin with an active synthetic analogue. 相似文献
14.
Rethinking Cysteine Protective Groups: S‐Alkylsulfonyl‐l‐Cysteines for Chemoselective Disulfide Formation
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Olga Schäfer Dr. David Huesmann Christian Muhl Dr. Matthias Barz 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(50):18085-18091
The ability to reversibly cross‐link proteins and peptides grants the amino acid cysteine its unique role in nature as well as in peptide chemistry. We report a novel class of S‐alkylsulfonyl‐l ‐cysteines and N‐carboxy anhydrides (NCA) thereof for peptide synthesis. The S‐alkylsulfonyl group is stable against amines and thus enables its use under Fmoc chemistry conditions and the controlled polymerization of the corresponding NCAs yielding well‐defined homo‐ as well as block co‐polymers. Yet, thiols react immediately with the S‐alkylsulfonyl group forming asymmetric disulfides. Therefore, we introduce the first reactive cysteine derivative for efficient and chemoselective disulfide formation in synthetic polypeptides, thus bypassing additional protective group cleavage steps. 相似文献
15.
Manuel G. Ricardo Celia G. Moya Carlos S. Prez Andrea Porzel Ludger A. Wessjohann Daniel G. Rivera 《Angewandte Chemie (International ed. in English)》2020,59(1):259-263
In contrast to the myriad of methods available to produce α‐helices and antiparallel β‐sheets in synthetic peptides, just a few are known for the construction of stable, non‐cyclic parallel β‐sheets. Herein, we report an efficient on‐resin approach for the assembly of parallel β‐sheet peptides in which the N‐alkylated turn moiety enhances the stability and gives access to a variety of functionalizations without modifying the parallel strands. The key synthetic step of this strategy is the multicomponent construction of an N‐alkylated turn using the Ugi reaction on varied isocyano‐resins. This four‐component process assembles the orthogonally protected turn fragment and incorporates handles serving for labeling/conjugation purposes or for reducing peptide aggregation. NMR and circular dichroism analyses confirm the better‐structured and more stable parallel β‐sheets in the N‐alkylated peptides compared to the non‐functionalized variants. 相似文献
16.
Controlling Peptide Self‐Assembly through a Native Chemical Ligation/Desulfurization Strategy
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Self‐assembled peptides were synthesized by using a native chemical ligation (NCL)/desulfurization strategy that maintained the chemical diversity of the self‐assembled peptides. Herein, we employed oxo‐ester‐mediated NCL reactions to incorporate cysteine, a cysteine‐based dipeptide, and a sterically hindered unnatural amino acid (penicillamine) into peptides. Self‐assembly of the peptides resulted in the formation of self‐supporting gels. Microscopy analysis indicated the formation of helical nanofibers, which were responsible for the formation of gel matrices. The self‐assembly of the ligated peptides was governed by covalent and non‐covalent interactions, as confirmed by FTIR, CD, fluorescence spectroscopy, and MS (ESI) analyses. Peptide disassembly was induced by desulfurization reactions with tris(2‐carboxyethyl)phosphine (TCEP) and glutathione at 80 °C. Desulfurization reactions of the ligated peptides converted the Cys and penicillamine functionalities into Ala and Val moieties, respectively. The self‐supporting gels showed significant shear‐thinning and thixotropic properties. 相似文献
17.
Kuntrapakam Hema Kana M. Sureshan 《Angewandte Chemie (International ed. in English)》2020,59(23):8854-8859
Protein‐mimics are of great interest for their structure, stability, and properties. We are interested in the synthesis of protein‐mimics containing triazole linkages as peptide‐bond surrogate by topochemical azide‐alkyne cycloaddition (TAAC) polymerization of azide‐ and alkyne‐modified peptides. The rationally designed dipeptide N3‐CH2CO‐Phe‐NHCH2CCH ( 1 ) crystallized in a parallel β‐sheet arrangement and are head‐to‐tail aligned in a direction perpendicular to the β‐sheet‐direction. Upon heating, crystals of 1 underwent single‐crystal‐to‐single‐crystal polymerization forming a triazole‐linked pseudoprotein with Gly‐Phe‐Gly repeats. During TAAC polymerization, the pseudoprotein evolved as helical chains. These helical chains are laterally assembled by backbone hydrogen bonding in a direction perpendicular to the helical axis to form helical sheets. This interesting helical‐sheet orientation in the crystal resembles the cross‐α‐amyloids, where α‐helices are arranged laterally as sheets. 相似文献
18.
Stabilization of the Cysteine‐Rich Conotoxin MrIA by Using a 1,2,3‐Triazole as a Disulfide Bond Mimetic
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Dr. Alessandro Gori Dr. Ching‐I A. Wang Dr. Peta J. Harvey Dr. K. Johan Rosengren Rebecca F. Bhola Prof. Maria L. Gelmi Renato Longhi Prof. Macdonald J. Christie Prof. Richard J. Lewis Prof. Paul F. Alewood Dr. Andreas Brust 《Angewandte Chemie (International ed. in English)》2015,54(4):1361-1364
The design of disulfide bond mimetics is an important strategy for optimising cysteine‐rich peptides in drug development. Mimetics of the drug lead conotoxin MrIA, in which one disulfide bond is selectively replaced of by a 1,4‐disubstituted‐1,2,3‐triazole bridge, are described. Sequential copper‐catalyzed azide–alkyne cycloaddition (CuAAC; click reaction) followed by disulfide formation resulted in the regioselective syntheses of triazole–disulfide hybrid MrIA analogues. Mimetics with a triazole replacing the Cys4–Cys13 disulfide bond retained tertiary structure and full in vitro and in vivo activity as norepinephrine reuptake inhibitors. Importantly, these mimetics are resistant to reduction in the presence of glutathione, thus resulting in improved plasma stability and increased suitability for drug development. 相似文献
19.
Site‐Selective Disulfide Modification of Proteins: Expanding Diversity beyond the Proteome
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Dr. Seah Ling Kuan Dr. Tao Wang Prof. Dr. Tanja Weil 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(48):17112-17129
The synthetic transformation of polypeptides with molecular accuracy holds great promise for providing functional and structural diversity beyond the proteome. Consequently, the last decade has seen an exponential growth of site‐directed chemistry to install additional features into peptides and proteins even inside living cells. The disulfide rebridging strategy has emerged as a powerful tool for site‐selective modifications since most proteins contain disulfide bonds. In this Review, we present the chemical design, advantages and limitations of the disulfide rebridging reagents, while summarizing their relevance for synthetic customization of functional protein bioconjugates, as well as the resultant impact and advancement for biomedical applications. 相似文献
20.
Structure–Activity Studies of Cysteine‐Rich α‐Conotoxins that Inhibit High‐Voltage‐Activated Calcium Channels via GABAB Receptor Activation Reveal a Minimal Functional Motif
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Dr. Bodil B. Carstens Dr. Géza Berecki James T. Daniel Han Siean Lee Kathryn A. V. Jackson Dr. Han‐Shen Tae Dr. Mahsa Sadeghi Dr. Joel Castro Tracy O'Donnell Dr. Annemie Deiteren Prof. Stuart M. Brierley Prof. David J. Craik Prof. David J. Adams Dr. Richard J. Clark 《Angewandte Chemie (International ed. in English)》2016,55(15):4692-4696
α‐Conotoxins are disulfide‐rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α‐conotoxins that also modulate voltage‐gated calcium channels by acting as G protein‐coupled GABAB receptor (GABABR) agonists. These α‐conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α‐conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α‐conotoxins known to inhibit high voltage‐activated calcium channels via GABABR activation. Remarkably, all disulfide isomers of the active α‐conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs. 相似文献