共查询到20条相似文献,搜索用时 0 毫秒
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Matthew W. Halloran Prof. Dr. Jean-Philip Lumb 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(19):4885-4898
The elucidation of substrate–protein interactions is an important component of the drug development process. Due to the complexity of native cellular environments, elucidating these fundamental biochemical interactions remains challenging. Photoaffinity labeling (PAL) is a versatile technique that can provide insight into ligand-target interactions. By judicious modification of substrates with a photoreactive group, PAL creates a covalent crosslink between a substrate and its biological target following UV-irradiation. Among the commonly employed photoreactive groups, diazirines have emerged as the gold standard. In this Minireview, recent developments in the field of diazirine-based photoaffinity labeling will be discussed, with emphasis being placed on their applications in chemical proteomic studies. 相似文献
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化学生物学新前沿——化学蛋白质组学 总被引:7,自引:0,他引:7
随着包括人类在内的主要模式生物的基因组计划的完成,生命科学的研究重心转向蛋白质组的研究--在对应基因组的整体蛋白质水平上系统研究调控细胞生命活动的蛋白质.化学蛋白质组学是化学生物学在后基因组时代的最新发展:化学蛋白质组学利用化学小分子为工具和手段,以基于靶蛋白质功能的新战略探测体内蛋白质组,是新一代的功能蛋白质组学.本文综述了化学蛋白质组学的最新进展、有关技术及其在生物医学和药物研发等方面的应用,并对化学蛋白质组学的发展趋势和前景进行了讨论. 相似文献
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《Angewandte Chemie (International ed. in English)》2017,56(5):1396-1401
Affinity‐based protein profiling (AfBPP) is a widely applied method for the target identification of bioactive molecules. Probes containing photocrosslinkers, such as benzophenones, diazirines, and aryl azides, irreversibly link the molecule of interest to its target protein upon irradiation with UV light. Despite their prevalent application, little is known about photocrosslinker‐specific off‐targets, affecting the reliability of results. Herein, we investigated background protein labeling by gel‐free quantitative proteomics. Characteristic off‐targets were identified for each photoreactive group and compiled in a comprehensive inventory. In a proof‐of‐principle study, H8 , a protein kinase A inhibitor, was equipped with a diazirine moiety. Application of this photoprobe revealed, by alignment with the diazirine background, unprecedented insight into its in situ proteome targets. Taken together, our findings guide the identification of biologically relevant binders in photoprobe experiments. 相似文献
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Cheng‐Long Gao Gui‐Ge Hou Jin Liu Tong Ru Ya‐Zhou Xu Shun‐Yi Zhao Hui Ye Lu‐Yong Zhang Kai‐Xian Chen Yue‐Wei Guo Tao Pang Xu‐Wen Li 《Angewandte Chemie (International ed. in English)》2020,59(6):2429-2439
Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior through anti‐inflammation in LPS‐induced neuroinflammatory mice model and cerebral ischemic injury through anti‐neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti‐inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti‐neuroinflammatory effect in vitro and in vivo by inhibiting PKM2‐mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation‐related diseases. 相似文献
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The main chemical approaches to the study of macromolecular structure and dynamics and to the elucidation of interbiopolymer
contact points are considered and illustrated by particular examples. Primary attention is paid to the chemical footprinting
and affinity modification methods. The use of bifunctional reagents for the study of nucleoprotein structure architecture
is described. The ways of enhancing the selectivity of affinity modification available from the literature are analyzed with
an emphasis on catalytically competent (superselective) labeling. The identification of proteins responsible for replication
of the tickborne encephalitis virus by this method is described to demonstrate the possibility of the application of the method
to multicomponent systems such as the nucleus fraction of infected cells.
Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1225–1231, July, 1999. 相似文献
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Satoshi Sakamoto Yasuaki Kabe Mamoru Hatakeyama Yuki Yamaguchi Hiroshi Handa 《Chemical record (New York, N.Y.)》2009,9(1):66-85
In drug development research, the elucidation and understanding of the interactions between physiologically active substances and proteins that numerous genes produce is important. Currently, most commercially available drugs and physiologically active substances have been brought to market without knowledge of factors interacting with the drugs and the substances. Affinity purification is a useful and powerful technique employed to understand factors that are targeted by drugs and physiologically active substances. However, use of conventional matrices for affinity chromatography often causes a decrease in efficiency of affinity purification and, as a result, more practical matrices for affinity purification have been developed for application in drug discovery research. In this paper, we describe the development of high‐performance affinity beads (SG beads and FG beads) that enable one‐step affinity purification of drug targets and the elucidation of the mechanism of the action of the drugs. We also describe a chemical screening system using our affinity beads. We hope that utilization of the affinity beads will contribute to the progress of research in chemical biology. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 66–85; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20170 相似文献
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Jongmin Park Dr. Sangmi Oh Prof. Seung Bum Park 《Angewandte Chemie (International ed. in English)》2012,51(22):5259-5259
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Quentin Spillier Sverine Ravez Simon Dochain Didier Vertommen Lopold Thabault Olivier Feron Raphaël Frdrick 《Molecules (Basel, Switzerland)》2021,26(2)
The serine biosynthetic pathway is a key element contributing to tumor proliferation. In recent years, targeting of phosphoglycerate dehydrogenase (PHGDH), the first enzyme of this pathway, intensified and revealed to be a promising strategy to develop new anticancer drugs. Among attractive PHGDH inhibitors are the α-ketothioamides. In previous work, we have demonstrated their efficacy in the inhibition of PHGDH in vitro and in cellulo. However, the precise site of action of this series, which would help the rational design of new inhibitors, remained undefined. In the present study, the detailed mechanism-of-action of a representative α-ketothioamide inhibitor is reported using several complementary experimental techniques. Strikingly, our work led to the identification of an allosteric site on PHGDH that can be targeted for drug development. Using mass spectrometry experiments and an original α-ketothioamide diazirine-based photoaffinity probe, we identified the 523Q-533F sequence on the ACT regulatory domain of PHGDH as the binding site of α-ketothioamides. Mutagenesis experiments further documented the specificity of our compound at this allosteric site. Our results thus pave the way for the development of new anticancer drugs using a completely novel mechanism-of-action. 相似文献
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Quentin T. L. Pasquer Ioannis A. Tsakoumagkos Sascha Hoogendoorn 《Molecules (Basel, Switzerland)》2020,25(23)
Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes. 相似文献
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