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Modulating Cell‐Surface Receptor Signaling and Ion Channel Functions by In Situ Glycan Editing 下载免费PDF全文
Dr. Hao Jiang Dr. Aimé López‐Aguilar Dr. Lu Meng Dr. Zhongwei Gao Dr. Yani Liu Xiao Tian Prof. Guangli Yu Dr. Ben Ovryn Prof. Kelley W. Moremen Prof. Peng Wu 《Angewandte Chemie (International ed. in English)》2018,57(4):967-971
Glycans anchored on cell‐surface receptors are active modulators of receptor signaling. A strategy is presented that enforces transient changes to cell‐surface glycosylation patterns to tune receptor signaling. This approach, termed in situ glycan editing, exploits recombinant glycosyltransferases to incorporate monosaccharides with linkage specificity onto receptors in situ. α2,3‐linked sialic acid or α1,3‐linked fucose added in situ suppresses signaling through epidermal growth factor receptor and fibroblast growth factor receptor. We also applied the same strategy to regulate the electrical signaling of a potassium ion channel–human ether‐à‐go‐go‐related gene channel. Compared to gene editing, no long‐term perturbations are introduced to the treated cells. In situ glycan editing therefore offers a promising approach for studying the dynamic role of specific glycans in membrane receptor signaling and ion channel functions. 相似文献
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Yaewon Kim Prof. Dr. Christian Hilty 《Angewandte Chemie (International ed. in English)》2015,54(16):4941-4944
Fluorine‐19 NMR and hyperpolarization form a powerful combination for drug screening. Under a competitive equilibrium with a selected fluorinated reporter ligand, the dissociation constant (KD) of other ligands of interest is measurable using a single‐scan Carr–Purcell–Meiboom–Gill (CPMG) experiment, without the need for a titration. This method is demonstrated by characterizing the binding of three ligands with different affinities for the serine protease trypsin. Monte Carlo simulations show that the highest accuracy is obtained when about one‐half of the bound reporter ligand is displaced in the binding competition. Such conditions can be achieved over a wide range of affinities, allowing for rapid screening of non‐fluorinated compounds when a single fluorinated ligand for the binding pocket of interest is known. 相似文献
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Structure‐Based Approach To Improve a Small‐Molecule Inhibitor by the Use of a Competitive Peptide Ligand 下载免费PDF全文
Dr. Katsuki Ono Dr. Koh Takeuchi Hiroshi Ueda Yasuhiro Morita Dr. Ryuji Tanimura Prof. Ichio Shimada Prof. Hideo Takahashi 《Angewandte Chemie (International ed. in English)》2014,53(10):2597-2601
Structural information about the target–compound complex is invaluable in the early stage of drug discovery. In particular, it is important to know into which part of the initial compound additional interaction sites could be introduced to improve its affinity. Herein, we demonstrate that the affinity of a small‐molecule inhibitor for its target protein could be successfully improved by the constructive introduction of the interaction mode of a competitive peptide. The strategy involved the discrimination of overlapping and non‐overlapping peptide–compound pharmacophores by the use of a ligand‐based NMR spectroscopic approach, INPHARMA. The obtained results enabled the design of a new compound with improved affinity for the platelet receptor glycoprotein VI (GPVI). The approach proposed herein efficiently combines the advantages of compounds and peptides for the development of higher‐affinity druglike ligands. 相似文献
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Application of Fragment‐Based Screening to the Design of Inhibitors of Escherichia coli DsbA 下载免费PDF全文
Dr. Luke A. Adams Dr. Pooja Sharma Dr. Biswaranjan Mohanty Olga V. Ilyichova Dr. Mark D. Mulcair Dr. Martin L. Williams Ellen C. Gleeson Dr. Makrina Totsika Dr. Bradley C. Doak Dr. Sofia Caria Dr. Kieran Rimmer Dr. James Horne Dr. Stephen R. Shouldice Mansha Vazirani Dr. Stephen J. Headey Brent R. Plumb Prof. Jennifer L. Martin Dr. Begoña Heras Dr. Jamie S. Simpson Dr. Martin J. Scanlon 《Angewandte Chemie (International ed. in English)》2015,54(7):2179-2184
The thiol‐disulfide oxidoreductase enzyme DsbA catalyzes the formation of disulfide bonds in the periplasm of Gram‐negative bacteria. DsbA substrates include proteins involved in bacterial virulence. In the absence of DsbA, many of these proteins do not fold correctly, which renders the bacteria avirulent. Thus DsbA is a critical mediator of virulence and inhibitors may act as antivirulence agents. Biophysical screening has been employed to identify fragments that bind to DsbA from Escherichia coli. Elaboration of one of these fragments produced compounds that inhibit DsbA activity in vitro. In cell‐based assays, the compounds inhibit bacterial motility, but have no effect on growth in liquid culture, which is consistent with selective inhibition of DsbA. Crystal structures of inhibitors bound to DsbA indicate that they bind adjacent to the active site. Together, the data suggest that DsbA may be amenable to the development of novel antibacterial compounds that act by inhibiting bacterial virulence. 相似文献
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Dr. Junhe Ma Qing Cao Dr. Sarah M. McLeod Keith Ferguson Ning Gao Prof. Alexander L. Breeze Dr. Jun Hu 《Angewandte Chemie (International ed. in English)》2015,54(16):4764-4767
An NMR‐based approach marries the two traditional screening technologies (phenotypic and target‐based screening) to find compounds inhibiting a specific enzymatic reaction in bacterial cells. Building on a previous study in which it was demonstrated that hydrolytic decomposition of meropenem in living Escherichia coli cells carrying New Delhi metallo‐β‐lactamase subclass 1 (NDM‐1) can be monitored in real time by NMR spectroscopy, we designed a cell‐based NMR screening platform. A strong NDM‐1 inhibitor was identified with cellular IC50 of 0.51 μM , which is over 300‐fold more potent than captopril, a known NDM‐1 inhibitor. This new screening approach has great potential to be applied to targets in other cell types, such as mammalian cells, and to targets that are only stable or functionally competent in the cellular environment. 相似文献
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In Situ Synthesis of Self‐Assembled Gold Nanoparticles on Glass or Silicon Substrates through Reactive Inkjet Printing 下载免费PDF全文
Mutalifu Abulikemu Eman Husni Da'as Dr. Hanna Haverinen Dr. Dongkyu Cha Dr. Mohammad Azad Malik Prof. Ghassan Elie Jabbour 《Angewandte Chemie (International ed. in English)》2014,53(2):420-423
A facile and low cost method for the synthesis of self‐assembled nanoparticles (NPs) with minimal size variation and chemical waste by using reactive inkjet printing was developed. Gold NPs with diameters as small as (8±2) nm can be made at low temperature (120 °C). The size of the resulting NPs can be readily controlled through the concentration of the gold precursor and oleylamine ink. The pure gold composition of the synthesized NPs was confirmed by energy‐dispersive X‐ray spectroscopy (EDXS) analysis. High‐resolution SEM (HRSEM) and TEM (HRTEM), and X‐ray diffraction revealed their size and face‐centered cubic (fcc) crystal structure, respectively. Owing to the high density of the NP film, UV/Vis spectroscopy showed a red shift in the intrinsic plasmonic resonance peak. We envision the extension of this approach to the synthesis of other nanomaterials and the production of tailored functional nanomaterials and devices. 相似文献
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Pengpeng Shao Ruxin Yao Ge Li Mengxi Zhang Shuai Yuan Xiaoqi Wang Yuhao Zhu Xianming Zhang Lin Zhang Xiao Feng Bo Wang 《Angewandte Chemie (International ed. in English)》2020,59(11):4401-4405
Commercial ultrafiltration membranes have proliferated globally for water treatment. However, their pore sizes are too large to sieve gases. Conjugated microporous polymers (CMPs) feature well‐developed microporosity yet are difficult to be fabricated into membranes. Herein, we report a strategy to prepare molecular‐sieving membranes by partitioning the mesoscopic channels in water ultrafiltration membrane (PSU) into ultra‐micropores by space‐confined polymerization of multi‐functionalized rigid building units. Nine CMP@PSU membranes were obtained, and their separation performance for H2/CO2, H2/N2, and H2/CH4 pairs surpass the Robeson upper bound and rival against the best of those reported membranes. Furthermore, highly crosslinked skeletons inside the channels result in the structural robustness and transfer into the excellent aging resistance of the CMP@PSU. This strategy may shed light on the design and fabrication of high‐performance polymeric gas separation membranes. 相似文献
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Real‐time Observation of Deep Lithiation of Tungsten Oxide Nanowires by In Situ Electron Microscopy 下载免费PDF全文
Kuo Qi Jiake Wei Muhua Sun Qianming Huang Xiaomin Li Zhi Xu Dr. Wenlong Wang Dr. Xuedong Bai 《Angewandte Chemie (International ed. in English)》2015,54(50):15222-15225
An in‐depth mechanistic understanding of the electrochemical lithiation process of tungsten oxide (WO3) is both of fundamental interest and relevant for potential applications. One of the most important features of WO3 lithiation is the formation of the chemically flexible, nonstoichiometric LixWO3, known as tungsten bronze. Herein, we achieved the real‐time observation of the deep electrochemical lithiation process of single‐crystal WO3 nanowires by constructing in situ transmission electron microscopy (TEM) electrochemical cells. As revealed by nanoscale imaging, diffraction, and spectroscopy, it is shown that the rapid and deep lithiation of WO3 nanowires leads to the formation of highly disordered and near‐amorphous LixWO3 phases, but with no detectable traces of elemental W and segregated Li2O phase formation. These results highlight the remarkable chemical and structural flexibility of the LixWO3 phases in accommodating the rapid and deep lithiation reaction. 相似文献
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Huawen Huang Jiuwu Wang Xianfeng Yang Renzong Hu Jinlong Liu Lei Zhang Min Zhu 《Angewandte Chemie (International ed. in English)》2020,59(34):14504-14510
Nanostructure design and in situ transmission electron microscopy (TEM) are combined to demonstrate Sb‐based nanofibers composed of bunched yolk–shell building units as a significantly improved anode for potassium‐ion batteries (PIBs). Particularly, a metal–organic frameworks (MOFs)‐engaged electrospinning strategy coupled to a confined ion‐exchange followed by a subsequent thermal reduction is proposed to fabricate yolk–shell Sb@C nanoboxes embedded in carbon nanofibers (Sb@CNFs). In situ TEM analysis reveals that the inner Sb nanoparticles undergo a significant volume expansion/contraction during the alloying/dealloying processes, while the void space can effectively relieve the overall volume change, and the plastic carbon shell maintains the structural integrity of electrode material. This work provides an important reference for the application of advanced characterization techniques to guide the optimization of electrode material design. 相似文献
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Exploring Weak Ligand–Protein Interactions by Long‐Lived NMR States: Improved Contrast in Fragment‐Based Drug Screening 下载免费PDF全文
Roberto Buratto Daniele Mammoli Dr. Elisabetta Chiarparin Dr. Glyn Williams Prof. Geoffrey Bodenhausen 《Angewandte Chemie (International ed. in English)》2014,53(42):11376-11380
Ligands that have an affinity for protein targets can be screened very effectively by exploiting favorable properties of long‐lived states (LLS) in NMR spectroscopy. In this work, we describe the use of LLS for competitive binding experiments to measure accurate dissociation constants of fragments that bind weakly to the ATP binding site of the N‐terminal ATPase domain of heat shock protein 90 (Hsp90), a therapeutic target for cancer treatment. The LLS approach allows one to characterize ligands with an exceptionally wide range of affinities, since it can be used for ligand concentrations [L] that are several orders of magnitude smaller than the dissociation constants KD. This property makes the LLS method particularly attractive for the initial steps of fragment‐based drug screening, where small molecular fragments that bind weakly to a target protein must be identified, which is a difficult task for many other biophysical methods. 相似文献
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Structure‐Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry 下载免费PDF全文
Milon Mondal Nedyalka Radeva Dr. Helene Köster Dr. Ahyoung Park Dr. Constantinos Potamitis Dr. Maria Zervou Prof. Dr. Gerhard Klebe Dr. Anna K. H. Hirsch 《Angewandte Chemie (International ed. in English)》2014,53(12):3259-3263
Structure‐based design (SBD) can be used for the design and/or optimization of new inhibitors for a biological target. Whereas de novo SBD is rarely used, most reports on SBD are dealing with the optimization of an initial hit. Dynamic combinatorial chemistry (DCC) has emerged as a powerful strategy to identify bioactive ligands given that it enables the target to direct the synthesis of its strongest binder. We have designed a library of potential inhibitors (acylhydrazones) generated from five aldehydes and five hydrazides and used DCC to identify the best binder(s). After addition of the aspartic protease endothiapepsin, we characterized the protein‐bound library member(s) by saturation‐transfer difference NMR spectroscopy. Cocrystallization experiments validated the predicted binding mode of the two most potent inhibitors, thus demonstrating that the combination of de novo SBD and DCC constitutes an efficient starting point for hit identification and optimization. 相似文献
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Chenge Li Alison G. Tebo Marion Thauvin Marie‐Aude Plamont Michel Volovitch Xavier Morin Sophie Vriz Arnaud Gautier 《Angewandte Chemie (International ed. in English)》2020,59(41):17917-17923
Far‐red emitting fluorescent labels are highly desirable for spectral multiplexing and deep tissue imaging. Here, we describe the generation of frFAST (far‐red Fluorescence Activating and absorption Shifting Tag), a 14‐kDa monomeric protein that forms a bright far‐red fluorescent assembly with (4‐hydroxy‐3‐methoxy‐phenyl)allylidene rhodanine (HPAR‐3OM). As HPAR‐3OM is essentially non‐fluorescent in solution and in cells, frFAST can be imaged with high contrast in presence of free HPAR‐3OM, which allowed the rapid and efficient imaging of frFAST fusions in live cells, zebrafish embryo/larvae, and chicken embryos. Beyond enabling the genetic encoding of far‐red fluorescence, frFAST allowed the design of a far‐red chemogenetic reporter of protein–protein interactions, demonstrating its great potential for the design of innovative far‐red emitting biosensors. 相似文献
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Francesco V. Reddavide Weilin Lin Sarah Lehnert Dr. Yixin Zhang 《Angewandte Chemie (International ed. in English)》2015,54(27):7924-7928
Dynamic combinatorial chemistry (DCC) explores the thermodynamic equilibrium of reversible reactions. Its application in the discovery of protein binders is largely limited by difficulties in the analysis of complex reaction mixtures. DNA‐encoded chemical library (DECL) technology allows the selection of binders from a mixture of up to billions of different compounds; however, experimental results often show low a signal‐to‐noise ratio and poor correlation between enrichment factor and binding affinity. Herein we describe the design and application of DNA‐encoded dynamic combinatorial chemical libraries (EDCCLs). Our experiments have shown that the EDCCL approach can be used not only to convert monovalent binders into high‐affinity bivalent binders, but also to cause remarkably enhanced enrichment of potent bivalent binders by driving their in situ synthesis. We also demonstrate the application of EDCCLs in DNA‐templated chemical reactions. 相似文献
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Inside Back Cover: In Situ Synthesis of Self‐Assembled Gold Nanoparticles on Glass or Silicon Substrates through Reactive Inkjet Printing (Angew. Chem. Int. Ed. 2/2014) 下载免费PDF全文
Mutalifu Abulikemu Eman Husni Da'as Dr. Hanna Haverinen Dr. Dongkyu Cha Dr. Mohammad Azad Malik Prof. Ghassan Elie Jabbour 《Angewandte Chemie (International ed. in English)》2014,53(2):599-599