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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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Rapid Determination of the Specificity Constant of Irreversible Inhibitors (kinact/KI) by Means of an Endpoint Competition Assay 下载免费PDF全文
Ikuo Miyahisa Dr. Tomoya Sameshima Dr. Mark S. Hixon 《Angewandte Chemie (International ed. in English)》2015,54(47):14099-14102
Owing to their covalent target occupancy, irreversible inhibitors require low exposures and offer long duration, and their use thus represents a powerful strategy for achieving pharmacological efficacy. Importantly, the potency metric of irreversible inhibitors is kinact/KI not IC50. A simple approach to measuring kinact/KI was developed that makes use of an irreversible probe for competitive assays run to completion against test compounds. In this system, the kinact/KI value of the test compound is equal to (kinact/KI)probe×[probe]/IC50. The advantages of this method include simplicity, high throughput, and application to all target classes, and it only requires an in‐depth kinetic evaluation of the probe. 相似文献
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Mohua Das Dr. Tianming Yang Jinghua Dong Fransisca Prasetya Yiming Xie Kendra H. Q. Wong Adeline Cheong Prof. Esther C. Y. Woon 《化学:亚洲杂志》2018,13(19):2854-2867
Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically templated DCC systems employ only a single biomolecule to direct the self‐assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic “thermal tag” with the sensitivity of differential scanning fluorimetry. This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily‐selective probes against two clinically important epigenetic enzymes: FTO ( 7 ; IC50=2.6 μm ) and ALKBH3 ( 8 ; IC50=3.7 μm ). To date, this is the first report of a subfamily‐selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest. 相似文献
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Markus Tiemann Dr. Eric Nawrotzky Dr. Peter Schmieder Leon Wehrhan Silke Bergemann Dr. Vera Martos Wei Song Dr. Christoph Arkona Prof. Dr. Bettina G. Keller Prof. Dr. Jörg Rademann 《Chemistry (Weinheim an der Bergstrasse, Germany)》2022,28(57):e202201282
Discovery of protein-binding fragments for precisely defined binding sites is an unmet challenge to date. Herein, formylglycine is investigated as a molecular probe for the sensitive detection of fragments binding to a spatially defined protein site . Formylglycine peptide 3 was derived from a phosphotyrosine-containing peptide substrate of protein tyrosine phosphatase PTP1B by replacing the phosphorylated amino acid with the reactive electrophile. Fragment ligation with formylglycine occurred in situ in aqueous physiological buffer. Structures and kinetics were validated by NMR spectroscopy. Screening and hit validation revealed fluorinated and non-fluorinated hit fragments being able to replace the native phosphotyrosine residue. The formylglycine probe identified low-affinity fragments with high spatial resolution as substantiated by molecular modelling. The best fragment hit, 4-amino-phenyl-acetic acid, was converted into a cellularly active, nanomolar inhibitor of the protein tyrosine phosphatase SHP2. 相似文献
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Pablo Martín‐Gago Christian A. Olsen 《Angewandte Chemie (International ed. in English)》2019,58(4):957-966
Selective covalent modification of a targeted protein is a powerful tool in chemical biology and drug discovery, with applications ranging from identification and characterization of proteins and their functions to the development of targeted covalent inhibitors. Most covalent ligands contain an affinity motif and an electrophilic warhead that reacts with a nucleophilic residue of the targeted protein. Because the electrophilic warhead is prone to react and modify off‐target nucleophiles, its reactivity should be balanced carefully to maximize target selectivity. Arylfluorosulfates have recently emerged as latent electrophiles for selective labeling of context‐specific tyrosine and lysine residues in protein pockets. Here, we review the recent but intense introduction of arylfluorosulfates into the arsenal of available warheads for selective covalent modification of proteins. We highlight the untapped potential of this functional group for use in chemical biology and drug discovery. 相似文献
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Shipeng He Guoqiang Dong Yu Li Shanchao Wu Wei Wang Chunquan Sheng 《Angewandte Chemie (International ed. in English)》2020,59(8):3028-3032
As one of the most aggressive and lethal human malignancies with extremely poor prognosis, there is an urgent demand of more effective therapy for the treatment of pancreatic cancer. Reported here is a new, effective therapeutic strategy and the design of small‐molecule inhibitors that simultaneously target bromodomain and extra‐terminal (BET) and histone deacetylase (HDAC), potentially serving as promising therapeutic agents for pancreatic cancer. A highly potent dual inhibitor ( 13 a ) is identified to possess excellent and balanced activities against BRD4 BD1 (IC50=11 nm ) and HDAC1 (IC50=21 nm ). Notably, this compound shows higher in vitro and in vivo antitumor potency than the BET inhibitor (+)‐JQ1 and the HDAC inhibitor vorinostat, either alone or and in combination, highlighting the advantages of BET/HDAC dual inhibitors for more effective treatment of pancreatic cancer. 相似文献
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Mark Damen Mario A. Izidoro Debora N. Okamoto Lilian C. G. Oliveira Helene I. V. Amatdjais-Groenen Stijn F. M. van Dongen Koen W. R. van Cleef Ronald P. van Rij Cindy E. J. Dieteren Daniel Girons Bernd N. M. van Buuren Byron E. E. Martina Albert D. M. E. Osterhaus Luiz Juliano Bob J. Scholte Martin C. Feiters 《Molecules (Basel, Switzerland)》2022,27(10)
Dengue is an important arboviral infectious disease for which there is currently no specific cure. We report gemini-like (geminoid) alkylated amphiphilic peptides containing lysines in combination with glycines or alanines (C15H31C(O)-Lys-(Gly or Ala)nLys-NHC16H33, shorthand notation C16-KXnK-C16 with X = A or G, and n = 0–2). The representatives with 1 or 2 Ala inhibit dengue protease and human furin, two serine proteases involved in dengue virus infection that have peptides with cationic amino acids as their preferred substrates, with IC50 values in the lower µM range. The geminoid C16-KAK-C16 combined inhibition of DENV2 protease (IC50 2.3 µM) with efficacy against replication of wildtype DENV2 in LLC-MK2 cells (EC50 4.1 µM) and an absence of toxicity. We conclude that the lysine-based geminoids have activity against dengue virus infection, which is based on their inhibition of the proteases involved in viral replication and are therefore promising leads to further developing antiviral therapeutics, not limited to dengue. 相似文献
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V. Baldoneschi Prof. S. Burgalassi Dr. D. Vullo Dr. A. Akdemir Dr. E. Dragoni A. Louka M. Mamusa Dr. D. Monti Prof. D. Berti Prof. E. Novellino Prof. G. De Rosa Prof. C. T. Supuran Prof. C. Nativi 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(5):1714-1721
Synthetic sulfonamide derivatives are a class of potent matrix metalloproteinase inhibitors (MMPI) that have potential for the treatment of diseases related to uncontrolled expression of these enzymes. The lack of selectivity of the large majority of such inhibitors, leading to the inhibition of MMPs in tissues other than the targeted one, has dramatically reduced the therapeutic interest in MMPIs. The recent development of efficient drug delivery systems that allow the transportation of a selected drug to its site of action has opened the way to new perspectives in the use of MMPIs. Here, a PAMAM‐based divalent dendron with two sulfonamidic residues was synthesized. This nanomolar inhibitor binds to the catalytic domain of two MMPs as well as to the transmembrane human carbonic anhydrases (hCAs) XII, which is present in the eye and considered an antiglaucoma target. In the animal model of an experimental dry eye, no occurrence of dotted staining in eyes treated with our inhibitor was observed, indicating no symptoms of corneal desiccation. 相似文献
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由于许多药物通过和生物体内的大分子(如蛋白质和核酸) 的选择性结合发挥效用, 因此快速、有效地发现靶分子的高亲和性配体成为各种药物发现方法的首要目标。在现代生物技术和NMR 技术高度发展的基础上产生的一种发现生物大分子高亲和性配体的新方法--SAR-by-NMR, 由于采用NMR 技术可以综合多种药物设计方法的优势, 能够在短时间内得到先导化合物, 从而大大加快了药物发现的速度并能节省大量的费用。本文介绍了SAR-by-NMR 发现高亲和性配体的基本原理、特点及其在药物发现中的应用。 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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Marie Hoarau Nattida Suwanakitti Thaveechai Varatthan Ratthiya Thiabma Roonglawan Rattanajak Netnapa Charoensetakul Emily K. Redman Tanatorn Khotavivattana Tirayut Vilaivan Yongyuth Yuthavong Sumalee Kamchonwongpaisan 《Molecules (Basel, Switzerland)》2022,27(11)
In the fight towards eradication of malaria, identifying compounds active against new drug targets constitutes a key approach. Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (PfHPPK) has been advanced as a promising target, as being part of the parasite essential folate biosynthesis pathway while having no orthologue in the human genome. However, no drug discovery efforts have been reported on this enzyme. In this study, we conducted a three-step screening of our in-house antifolate library against PfHPPK using a newly designed PfHPPK-GFP protein construct. Combining virtual screening, differential scanning fluorimetry and enzymatic assay, we identified 14 compounds active against PfHPPK. Compounds’ binding modes were investigated by molecular docking, suggesting competitive binding with the HMDP substrate. Cytotoxicity and in vitro ADME properties of hit compounds were also assessed, showing good metabolic stability and low toxicity. The most active compounds displayed low micromolar IC50 against drug-resistant parasites. The reported hit compounds constitute a good starting point for inhibitor development against PfHPPK, as an alternative approach to tackle the malaria parasite. 相似文献
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Kanna Adachi Tomoshi Yamada Hayate Ishizuka Mana Oki Shunsuke Tsunogae Noriko Shimada Osamu Chiba Tatsuya Orihara Prof. Dr. Masafumi Hidaka Prof. Dr. Takatsugu Hirokawa Dr. Minami Odagi Prof. Dr. Keiichi Konoki Prof. Dr. Mari Yotsu-Yamashita Prof. Dr. Kazuo Nagasawa 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(9):2025-2033
A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV-inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX ( 3 a ) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV1.5, with an IC50 value of 94.1 nm . Derivatives 3 a – d and 3 f showed low recovery rates from NaV1.2 subtype (ca 45–79 %) compared to natural dcSTX ( 2 ), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717. 相似文献
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Rationally Designed Semisynthetic Natural Product Analogues for Stabilization of 14‐3‐3 Protein–Protein Interactions 下载免费PDF全文
Sebastian A. Andrei Pim de Vink Eline Sijbesma Ling Han Prof. Luc Brunsveld Prof. Nobuo Kato Prof. Christian Ottmann Dr. Yusuke Higuchi 《Angewandte Chemie (International ed. in English)》2018,57(41):13470-13474
The natural product family of fusicoccanes are stabilizers of 14‐3‐3 mediated protein–protein interactions (PPIs), some of which possess antitumor activity. In this study, the first use of molecular dynamics (MD) to rationally design PPI stabilizers with increased potency is presented. Synthesis of a focused library, with subsequent characterization by fluorescence polarization, mutational studies, and X‐ray crystallography confirmed the power of the MD‐based design approach, revealing the potential for an additional hydrogen bond with the 14‐3‐3 protein to lead to significantly increased potency. Additionally, these compounds exert their action in a cellular environment with increased potency. The newly found polar interaction could provide an anchoring point for new small‐molecule PPI stabilizers. These results facilitate the development of fusicoccanes towards drugs or tool compounds, as well as allowing the study of the fundamental principles behind PPI stabilization. 相似文献
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Dr. Jonas Aretz Hannes Baukmann Elena Shanina Dr. Jonas Hanske Dr. Robert Wawrzinek Dr. Viktor A. Zapol'skii Prof. Dr. Peter H. Seeberger Prof. Dr. Dieter E. Kaufmann Dr. Christoph Rademacher 《Angewandte Chemie (International ed. in English)》2017,56(25):7292-7296
DC-SIGN is a cell-surface receptor for several pathogenic threats, such as HIV, Ebola virus, or Mycobacterium tuberculosis. Multiple attempts to develop inhibitors of the underlying carbohydrate–protein interactions have been undertaken in the past fifteen years. Still, drug-like DC-SIGN ligands are sparse, which is most likely due to its hydrophilic, solvent-exposed carbohydrate-binding site. Herein, we report on a parallel fragment screening against DC-SIGN applying SPR and a reporter displacement assay, which complements previous screenings using 19F NMR spectroscopy and chemical fragment microarrays. Hit validation by SPR and 1H–15N HSQC NMR spectroscopy revealed that although no fragment bound in the primary carbohydrate site, five secondary sites are available to harbor drug-like molecules. Building on key interactions of the reported fragment hits, these pockets will be targeted in future approaches to accelerate the development of DC-SIGN inhibitors. 相似文献
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Dr. Chiara Platella Dr. Ettore Napolitano Dr. Claudia Riccardi Prof. Domenica Musumeci Prof. Daniela Montesarchio 《ChemistryOpen》2022,11(5):e202200090
DNA G-quadruplexes (G4s) are key structures for the development of targeted anticancer therapies. In this context, ligands selectively interacting with G4s can represent valuable anticancer drugs. Aiming at speeding up the identification of G4-targeting synthetic or natural compounds, we developed an affinity chromatography-based assay, named G-quadruplex on Oligo Affinity Support (G4-OAS), by synthesizing G4-forming sequences on commercially available polystyrene OAS. Then, due to unspecific binding of several hydrophobic ligands on nude OAS, we moved to Controlled Pore Glass (CPG). We thus conceived an ad hoc functionalized, universal support on which both the on-support elongation and deprotection of the G4-forming oligonucleotides can be performed, along with the successive affinity chromatography-based assay, renamed as G-quadruplex on Controlled Pore Glass (G4-CPG) assay. Here we describe these assays and their applications to the screening of several libraries of chemically different putative G4 ligands. Finally, ongoing studies and outlook of our G4-CPG assay are reported. 相似文献
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A Horatscheck S Wagner J Ortwein BG Kim M Lisurek S Beligny A Schütz J Rademann 《Angewandte Chemie (International ed. in English)》2012,51(37):9441-9447
A light switch for phosphotyrosine- recognizing proteins: Irradiation of the bioisosteric benzoylphosphonate suffices to "turn off" the activity of target proteins and to label them covalently. Photoactive bioisosters may find applications in functional cell biology, bioanalytics, and proteome research. 相似文献