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A One‐Pot Chemically Cleavable Bis‐Linker Tether Strategy for the Synthesis of Heterodimeric Peptides 下载免费PDF全文
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
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Synthesis of Sulfotyrosine‐Containing Peptides by Incorporating Fluorosulfated Tyrosine Using an Fmoc‐Based Solid‐Phase Strategy 下载免费PDF全文
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
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A General Approach Towards Triazole‐Linked Adenosine Diphosphate Ribosylated Peptides and Proteins 下载免费PDF全文
Qiang Liu Dr. Hans A. V. Kistemaker Dr. Sagar Bhogaraju Prof. Dr. Ivan Dikic Prof. Dr. Herman S. Overkleeft Prof. Dr. Gijsbert A. van der Marel Prof. Dr. Huib Ovaa Dr. Gerbrand J. van der Heden van Noort Dr. Dmitri V. Filippov 《Angewandte Chemie (International ed. in English)》2018,57(6):1659-1662
Current methods to prepare adenosine diphosphate ribosylated (ADPr) peptides are not generally applicable due to the labile nature of this post‐translational modification and its incompatibility with strong acidic conditions used in standard solid‐phase peptide synthesis. A general strategy is presented to prepare ADPr peptide analogues based on a copper‐catalyzed click reaction between an azide‐modified peptide and an alkyne‐modified ADPr counterpart. The scope of this approach was expanded to proteins by preparing two ubiquitin ADPr analogues carrying the biological relevant α‐glycosidic linkage. Biochemical validation using Legionella effector enzyme SdeA shows that clicked ubiquitin ADPr is well‐tolerated and highlights the potential of this strategy to prepare ADPr proteins. 相似文献
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Quaternary β2,2‐Amino Acids: Catalytic Asymmetric Synthesis and Incorporation into Peptides by Fmoc‐Based Solid‐Phase Peptide Synthesis 下载免费PDF全文
Dr. Jin‐Sheng Yu Dr. Hidetoshi Noda Prof. Dr. Masakatsu Shibasaki 《Angewandte Chemie (International ed. in English)》2018,57(3):818-822
β‐Amino acid incorporation has emerged as a promising approach to enhance the stability of parent peptides and to improve their biological activity. Owing to the lack of reliable access to β2,2‐amino acids in a setting suitable for peptide synthesis, most contemporary research efforts focus on the use of β3‐ and certain β2,3‐amino acids. Herein, we report the catalytic asymmetric synthesis of β2,2‐amino acids and their incorporation into peptides by Fmoc‐based solid‐phase peptide synthesis (Fmoc‐SPPS). A quaternary carbon center was constructed by the palladium‐catalyzed decarboxylative allylation of 4‐substituted isoxazolidin‐5‐ones. The N?O bond in the products not only acts as a traceless protecting group for β‐amino acids but also undergoes amide formation with α‐ketoacids derived from Fmoc‐protected α‐amino acids, thus providing expeditious access to α‐β2,2‐dipeptides ready for Fmoc‐SPPS. 相似文献
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Solid‐Phase Thiol–Ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist 下载免费PDF全文
Elyse T. Williams Dr. Paul W. R. Harris Muhammad A. Jamaluddin Dr. Kerry M. Loomes Prof. Debbie L. Hay Prof. Margaret A. Brimble 《Angewandte Chemie (International ed. in English)》2018,57(36):11640-11643
We report a new method herein coined SP‐CLipPA (solid‐phase cysteine lipidation of a peptide or amino acid) for the synthesis of mono‐S‐lipidated peptides. This technique utilizes thiol–ene chemistry for conjugation of a vinyl ester to a free thiol of a semiprotected, resin‐bound peptide. Advantages of SP‐CLipPA include: ease of handling, conversions of up to 91 %, by‐product removal by simple filtration, and a single purification step. Additionally, the desired lipidated products show high chromatographic separation from impurities, thus facilitating RP‐HPLC purification. To showcase the utility of SP‐CLipPA, we synthesized a potent calcitonin gene‐related peptide (CGRP) receptor antagonist peptide in excellent yield and purity. This peptide, selected from a series of lipidated analogues of CGRP8–37 and CGRP7–37, has potential for the treatment of migraine. 相似文献
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Inside Cover: A One‐Pot Chemically Cleavable Bis‐Linker Tether Strategy for the Synthesis of Heterodimeric Peptides (Angew. Chem. Int. Ed. 47/2016) 下载免费PDF全文
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):14472-14472
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Construction of a High‐Mannose‐Type Glycan Library by a Renewed Top‐Down Chemo‐Enzymatic Approach 下载免费PDF全文
Dr. Kohki Fujikawa Dr. Akihiko Koizumi Dr. Masakazu Hachisu Dr. Akira Seko Dr. Yoichi Takeda Dr. Yukishige Ito 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(8):3224-3233
A comprehensive method for the construction of a high‐mannose‐type glycan library by systematic chemo‐enzymatic trimming of a single Man9‐based precursor was developed. It consists of the chemical synthesis of a non‐natural tridecasaccharide precursor, the orthogonal demasking of the non‐reducing ends, and trimming by glycosidases, which enabled a comprehensive synthesis of high‐mannose‐type glycans in their mono‐ or non‐glucosylated forms. It employed glucose, isopropylidene, and N‐acetylglucosamine groups for blocking the A‐, B‐, and C‐arms, respectively. After systematic trimming of the precursor, thirty‐seven high‐mannose‐type glycans were obtained. The power of the methodology was demonstrated by the enzymatic activity of human recombinant N‐acetylglucosaminyltransferase‐I toward M7–M3 glycans, clarifying the substrate specificity in the context of high‐mannose‐type glycans. 相似文献
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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
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Chain‐Terminating and Clickable NAD+ Analogues for Labeling the Target Proteins of ADP‐Ribosyltransferases 下载免费PDF全文
Yan Wang Daniel Rösner Magdalena Grzywa Prof. Dr. Andreas Marx 《Angewandte Chemie (International ed. in English)》2014,53(31):8159-8162
ADP‐ribosyltransferases (ARTs) use NAD+ as a substrate and play important roles in numerous biological processes, such as the DNA damage response and cell cycle regulation, by transferring multiple ADP‐ribose units onto target proteins to form poly(ADP‐ribose) (PAR) chains of variable sizes. Efforts to identify direct targets of PARylation, as well as the specific ADP‐ribose acceptor sites, must all tackle the complexity of PAR. Herein, we report new NAD+ analogues that are efficiently processed by wild‐type ARTs and lead to chain termination owing to a lack of the required hydroxy group, thereby significantly reducing the complexity of the protein modification. Due to the presence of an alkyne group, these NAD+ analogues allow subsequent manipulations by click chemistry for labeling with dyes or affinity markers. This study provides insight into the substrate scope of ARTs and might pave the way for the further developments of chemical tools for investigating PAR metabolism. 相似文献
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Manuel G. Ricardo Dayma Llanes Ludger A. Wessjohann Daniel G. Rivera 《Angewandte Chemie (International ed. in English)》2019,58(9):2700-2704
For the first time, the Petasis (borono‐Mannich) reaction is employed for the multicomponent labeling and stapling of peptides. The report includes the solid‐phase derivatization of peptides at the N‐terminus, Lys, and N?‐MeLys side‐chains by an on‐resin Petasis reaction with variation of the carbonyl and boronic acid components. Peptides were simultaneously functionalized with aryl/vinyl substituents bearing fluorescent/affinity tags and oxo components such as dihydroxyacetone, glyceraldehyde, glyoxylic acid, and aldoses, thus encompassing a powerful complexity‐generating approach without changing the charge of the peptides. The multicomponent stapling was conducted in solution by linking N?‐MeLys or Orn side‐chains, positioned at i, i+7 and i, i+4, with aryl tethers, while hydroxy carbonyl moieties were introduced as exocyclic fragments. The good efficiency and diversity oriented character of these methods show prospects for peptide drug discovery and chemical biology. 相似文献
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Hiroaki Itoh Kensuke Miura Koichi Kamiya Tomoya Yamashita Masayuki Inoue 《Angewandte Chemie (International ed. in English)》2020,59(11):4564-4571
We report a solid‐phase strategy for total synthesis of the peptidic natural product yaku'amide B ( 1 ), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues and is capped with an N‐terminal acyl group (NTA) and a C‐terminal amine (CTA). To realize the Fmoc‐based solid‐phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C‐terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)3 led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin‐cleavage and C‐terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe3 to deliver 1 in 9.1 % overall yield (24 steps from the resin). 相似文献
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Dr. Simon Gregersen Prof. Dr. Tom Vosch Prof. Dr. Knud J. Jensen 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(51):18492-18500
Few‐atom silver nanoclusters (AgNCs) can exhibit strong fluorescence; however, they require ligands to prevent aggregation into larger nanoparticles. Fluorescent AgNCs in biopolymer scaffolds have so far mainly been synthesized in solution, and peptides have only found limited use compared to DNA. Herein, we demonstrate how solid‐phase methods can increase throughput dramatically in peptide ligand screening and in initial evaluation of fluorescence intensity and chemical stability of peptide‐stabilized AgNCs (P‐AgNCs). 9‐Fluorenylmethyloxycarbonyl (Fmoc) solid‐phase peptide synthesis on a hydroxymethyl‐benzoic acid (HMBA) polyethylene glycol polyacrylamide copolymer (PEGA) resin enabled on‐resin screening and evaluation of a peptide library, leading to identification of novel peptide‐stabilized, fluorescent AgNCs. Using systematic amino acid substitutions, we synthesized and screened a 144‐member library. This allowed us to evaluate the effect of length, charge, and Cys content in peptides used as ligands for AgNC stabilization. The results of this study will enable future spectroscopic studies of these peptide‐stabilized AgNCs for bioimaging and other applications. 相似文献
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Total Chemical Synthesis of SUMO and SUMO‐Based Probes for Profiling the Activity of SUMO‐Specific Proteases 下载免费PDF全文
Dr. Monique P. C. Mulder Dr. Remco Merkx Katharina F. Witting Dharjath S. Hameed Dris El Atmioui Lindsey Lelieveld Frauke Liebelt Prof. Dr. Jacques Neefjes Dr. Ilana Berlin Dr. Alfred C. O. Vertegaal Prof. Dr. Huib Ovaa 《Angewandte Chemie (International ed. in English)》2018,57(29):8958-8962
SUMO is a post‐translational modifier critical for cell cycle progression and genome stability that plays a role in tumorigenesis, thus rendering SUMO‐specific enzymes potential pharmacological targets. However, the systematic generation of tools for the activity profiling of SUMO‐specific enzymes has proven challenging. We developed a diversifiable synthetic platform for SUMO‐based probes by using a direct linear synthesis method, which permits N‐ and C‐terminal labelling to incorporate dyes and reactive warheads, respectively. In this manner, activity‐based probes (ABPs) for SUMO‐1, SUMO‐2, and SUMO‐3‐specific proteases were generated and validated in cells using gel‐based assays and confocal microscopy. We further expanded our toolbox with the synthesis of a K11‐linked diSUMO‐2 probe to study the proteolytic cleavage of SUMO chains. Together, these ABPs demonstrate the versatility and specificity of our synthetic SUMO platform for in vitro and in vivo characterization of the SUMO protease family. 相似文献
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Qian Qu Shuai Gao Fangming Wu Meng‐Ge Zhang Ying Li Long‐Hua Zhang Donald Bierer Chang‐Lin Tian Ji‐Shen Zheng Lei Liu 《Angewandte Chemie (International ed. in English)》2020,59(15):6037-6045
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