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101.
Mike Jaegle Ee Lin Wong Carolin Tauber Eric Nawrotzky Dr. Christoph Arkona Prof. Dr. Jörg Rademann 《Angewandte Chemie (International ed. in English)》2017,56(26):7358-7378
Protein-templated fragment ligation is a novel concept to support drug discovery and can help to improve the efficacy of protein ligands. Protein-templated fragment ligations are chemical reactions between small molecules (“fragments”) utilizing a protein's surface as a reaction vessel to catalyze the formation of a protein ligand with increased binding affinity. The approach exploits the molecular recognition of reactive small-molecule fragments by proteins both for ligand assembly and for the identification of bioactive fragment combinations. In this way, chemical synthesis and bioassay are integrated in one single step. This Review discusses the biophysical basis of reversible and irreversible fragment ligations and gives an overview of the available methods to detect protein-templated ligation products. The chemical scope and recent applications as well as future potential of the concept in drug discovery are reviewed. 相似文献
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Dr. Yaron Bram Ayala Lampel Dr. Ronit Shaltiel‐Karyo Anat Ezer Dr. Roni Scherzer‐Attali Prof. Dr. Daniel Segal Prof. Dr. Ehud Gazit 《Angewandte Chemie (International ed. in English)》2015,54(7):2062-2067
Amyloid deposits are pathological hallmark of a large group of human degenerative disorders of unrelated etiologies. While accumulating evidence suggests that early oligomers may account for tissue degeneration, most detection tools do not allow the monitoring of early association events. Here we exploit bimolecular fluorescence complementation analysis to detect and quantify the dimerization of three major amyloidogenic polypeptides; islet amyloid polypeptide, β‐amyloid and α‐synuclein. The constructed systems provided direct visualization of protein‐protein interactions in which only assembled dimers display strong fluorescent signal. Potential inhibitors that interfere with the initial intermolecular interactions of islet amyloid polypeptide were further identified using this system. Moreover, the identified compounds were able to inhibit the aggregation and cytotoxicity of islet amyloid polypeptide, demonstrating the importance of targeting amyloid dimer formation for future drug development. 相似文献
105.
Nessa Carson 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(15):3194-3196
High-throughput experimentation (HTE) is a growing, enabling technology that allows the execution of large, parallel sets of experiments. Often, automation is required to dose compounds on milligram to sub-milligram scale, to run many parallel reactions, and to analyse large datasets. Unique approaches to screen design, implementation, and analysis are required, distinct from traditional synthetic organic chemistry. The discipline also presents a profitable opportunity for individual scientists to learn about and explore fields adjacent to chemistry, including data science, robotics and equipment engineering, and computer programming. This perspective presents the author's viewpoints on the field of HTE, its implementation within a chemistry career, and the automated future of organic chemistry technology. 相似文献
106.
Cheng Weng Linghui Shen Prof. Dr. Wee Han Ang 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(24):9400-9404
The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination-directed 3-component assembly to prepare a library of 768 unique Ru–Arene Schiff-base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites. 相似文献
107.
Matthew G. Alteen Dr. Christina Gros Dr. Richard W. Meek David A. Cardoso Jil A. Busmann Gontran Sangouard Matthew C. Deen Hong-Yee Tan David L. Shen Cecilia C. Russell Prof. Gideon J. Davies Prof. Phillip J. Robinson Prof. Adam McCluskey Prof. David J. Vocadlo 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(24):9688-9696
Glycosyltransferases carry out important cellular functions in species ranging from bacteria to humans. Despite their essential roles in biology, simple and robust activity assays that can be easily applied to high-throughput screening for inhibitors of these enzymes have been challenging to develop. Herein, we report a bead-based strategy to measure the group-transfer activity of glycosyltransferases sensitively using simple fluorescence measurements, without the need for coupled enzymes or secondary reactions. We validate the performance and accuracy of the assay using O-GlcNAc transferase (OGT) as a model system through detailed Michaelis–Menten kinetic analysis of various substrates and inhibitors. Optimization of this assay and application to high-throughput screening enabled screening for inhibitors of OGT, leading to a novel inhibitory scaffold. We believe this assay will prove valuable not only for the study of OGT, but also more widely as a general approach for the screening of glycosyltransferases and other group-transfer enzymes. 相似文献
108.
The homing properties of adipose tissue-derived mesenchymal stem cells (AdMSCs) have stimulated intravenous applications for their use in stem cell therapy. However, the soluble factors and corresponding cellular receptors responsible for inducing chemotaxis of AdMSCs have not yet been reported. In the present study, the migration capacity of human AdMSCs (hAdMSCs) toward various cytokines or growth factors (GFs) and the expression of their receptors were determined. In a conventional migration assay, PDGF-AB, TGF-β1, and TNF-α showed the most effective chemoattractant activity. When AdMSCs were preincubated with various chemokines or GF, and then allowed to migrate toward medium containing 10% FBS, those preincubated with TNF-α showed the highest migratory activity. Next, hAdMSCs were either preincubated or not with TNF-α, and allowed to migrate in response to various GFs or chemokines. Prestimulation with TNF-α increased the migration activity of hAdMSCs compared to unstimulated hAdMSCs. When analyzed by FACS and RT-PCR methods, hAdMSCs were found to express C-C chemokine receptor type 1 (CCR1), CCR7, C-X-C chemokine receptor type 4 (CXCR4), CXCR5, CXCR6, EGF receptor, fibroblast growth factor receptor 1, TGF-β receptor 2, TNF receptor superfamily member 1A, PDGF receptor A and PDGF receptor B at both the protein and the mRNA levels. These results indicate that the migration capacity of hAdMSCs is controlled by various GFs and chemokines. Prior in vitro modulation of the homing capacity of hAdMSCs could stimulate their movement into injured sites in vivo when administered intravenously, thereby improving their therapeutic potential. 相似文献
109.
Sheila C. Araujo Fernanda S. Sousa Thais A. Costa-Silva Andre G. Tempone Joo Henrique G. Lago Kathia M. Honorio 《Molecules (Basel, Switzerland)》2021,26(14)
In the present study, the phytochemical study of the n-hexane extract from flowers of Nectandra leucantha (Lauraceae) afforded six known neolignans (1–6) as well as one new metabolite (7), which were characterized by analysis of NMR, IR, UV, and ESI-HRMS data. The new compound 7 exhibited potent activity against the clinically relevant intracellular forms of T. cruzi (amastigotes), with an IC50 value of 4.3 μM and no observed mammalian cytotoxicity in fibroblasts (CC50 > 200 μM). Based on the results obtained and our previous antitrypanosomal data of 50 natural and semi-synthetic related neolignans, 2D and 3D molecular modeling techniques were employed to help the design of new neolignan-based compounds with higher activity. The results obtained from the models were important to understand the main structural features related to the biological response of the neolignans and to aid in the design of new neolignan-based compounds with better biological activity. Therefore, the results acquired from phytochemical, biological, and in silico studies showed that the integration of experimental and computational techniques consists of a powerful tool for the discovery of new prototypes for development of new drugs to treat CD. 相似文献
110.
Lizandra Maria Zimmermann-Dimer 《Tetrahedron》2009,65(21):4239-641
Three merocyanine dyes (two pyridiniophenolates and Brooker's merocyanine) were dissolved in trichloromethane in their protonated form, and their potential as anionic chromogenic chemosensors was explored by adding various anions. The experimental data collected were treated considering a model based on the proton transfer from the protonated dye to the anion. One of the dyes was used in the development of an anionic colorimetric assay based on a trichloromethane-water biphasic system, which was able to selectively detect cyanide among other anionic species. 相似文献