共查询到20条相似文献,搜索用时 60 毫秒
1.
Assist. Prof. Luca Laraia Dr. Guillaume Garivet Dr. Daniel J. Foley Dr. Nadine Kaiser Dr. Sebastian Müller M. Sc. Sarah Zinken Thomas Pinkert M. Sc. Julian Wilke Dr. Dale Corkery Dr. Axel Pahl Dr. Sonja Sievers Dr. Petra Janning Prof. Dr. Christoph Arenz Prof. Yaowen Wu Prof. Raphaël Rodriguez Prof. Dr. Herbert Waldmann 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(14):5770-5778
Chemical proteomics is widely applied in small-molecule target identification. However, in general it does not identify non-protein small-molecule targets, and thus, alternative methods for target identification are in high demand. We report the discovery of the autophagy inhibitor autoquin and the identification of its molecular mode of action using image-based morphological profiling in the cell painting assay. A compound-induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. In addition, autoquin sequesters Fe2+ in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. Such a mechanism of action would have been challenging to unravel by current methods. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules, warranting wider application in chemical biology. 相似文献
2.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(42):13201-13205
Cell‐based assays enable monitoring of small‐molecule bioactivity in a target‐agnostic manner and help uncover new biological mechanisms. Subsequent identification and validation of the small‐molecule targets, typically employing proteomics techniques, is very challenging and limited, in particular if the targets are membrane proteins. Herein, we demonstrate that the combination of cell‐based bioactive‐compound discovery with cheminformatic target prediction may provide an efficient approach to accelerate the process and render target identification and validation more efficient. Using a cell‐based assay, we identified the pyrazolo‐imidazole smoothib as a new inhibitor of hedgehog (Hh) signaling and an antagonist of the protein smoothened (SMO) with a novel chemotype. Smoothib targets the heptahelical bundle of SMO, prevents its ciliary localization, reduces the expression of Hh target genes, and suppresses the growth of Ptch+/− medulloblastoma cells. 相似文献
3.
Daniel J. Foley Sarah Zinken Dale Corkery Luca Laraia Axel Pahl Yao‐Wen Wu Herbert Waldmann 《Angewandte Chemie (International ed. in English)》2020,59(30):12470-12476
Pseudo‐natural‐product (NP) design combines natural product fragments to provide unprecedented NP‐inspired compounds not accessible by biosynthesis, but endowed with biological relevance. Since the bioactivity of pseudo‐NPs may be unprecedented or unexpected, they are best evaluated in target agnostic cell‐based assays monitoring entire cellular programs or complex phenotypes. Here, the Cinchona alkaloid scaffold was merged with the indole ring system to synthesize indocinchona alkaloids by Pd‐catalyzed annulation. Exploration of indocinchona alkaloid bioactivities in phenotypic assays revealed a novel class of azaindole‐containing autophagy inhibitors, the azaquindoles. Subsequent characterization of the most potent compound, azaquindole‐1, in the morphological cell painting assay, guided target identification efforts. In contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation‐ and rapamycin‐induced autophagy by targeting the lipid kinase VPS34. 相似文献
4.
《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2017,129(51):16436-16440
Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell‐free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18F‐isotopologue validated our liver‐targeting approach. 相似文献
5.
Hideki Yorimitsu Dr. Yoshihiro Murakami Dr. Hiroyuki Takamatsu Dr. Shintaro Nishimura Dr. Eiichi Nakamura Prof. Dr. 《化学:亚洲杂志》2007,2(1):57-65
In positron emission tomography (PET), which exploits the affinity of a radiopharmaceutical for the target organ, a systematic repertoire of oxygen‐15‐labeled PET tracers is expected to be useful for bioimaging owing to the ubiquity of oxygen atoms in organic compounds. However, because of the 2‐min half‐life of 15O, the synthesis of complex biologically active 15O‐labeled organic molecules has not yet been achieved. A state‐of‐the‐art synthesis now makes available an 15O‐labeled complex organic molecule, 6‐[15O]‐2‐deoxy‐D ‐glucose. Ultrarapid radical hydroxylation of 2,6‐dideoxy‐6‐iodo‐D ‐glucose with molecular oxygen labeled with 15O of two‐minute half‐life provided the target 15O‐labeled molecule. The labeling reaction with 15O was complete in 1.3 min, and the entire operation time starting from the generation of 15O‐containing dioxygen by a cyclotron to the purification of the labeled sugar was 7 min. The labeled sugar accumulated in the metabolically active organs as well as in the bladder of mice and rats. 15O‐labeling offers the possibility of repetitive scanning and the use of multiple PET tracers in the same body within a short time, and hence should significantly expand the scope of PET studies of small animals. 相似文献
6.
A DNA‐Mediated Chemically Induced Dimerization (D‐CID) Nanodevice for Nongenetic Receptor Engineering To Control Cell Behavior 下载免费PDF全文
Hao Li Miao Wang Tianhui Shi Sihui Yang Jinghui Zhang Prof. Hong‐Hui Wang Prof. Zhou Nie 《Angewandte Chemie (International ed. in English)》2018,57(32):10226-10230
Small‐molecule regulation is a powerful switching tool to manipulate cell signal transduction for a desired function; however, most available methods usually require genetic engineering to endow cells with responsiveness to user‐defined small molecules. Herein, we demonstrate a nongenetic approach for small‐molecule‐controlled receptor activation and consequent cell behavior manipulation that is based on DNA‐mediated chemically induced dimerization (D‐CID). D‐CID uses a programmable chemical‐responsive DNA nanodevice to trigger DNA strand displacement and induce the activation of c‐Met, a tyrosine kinase receptor cognate for hepatocyte growth factor, through dimerization. Through the use of various functional nucleic acids, including aptamers and DNAzymes, as recognition modules, the versatility of D‐CID in inducing c‐Met signaling upon addition of various small‐molecular or ionic cues, including ATP, histidine, and Zn2+, is demonstrated. Moreover, owing its multi‐input properties, D‐CID can be used to manipulate the behaviors of multiple cell populations simultaneously in a selective and programmable fashion. 相似文献
7.
The N‐acylsulfonamide group, known as a safety‐catch linker, has been applied to photoaffinity labeling (PAL) using a cinnamate‐type photocrosslinker to improve the efficiency of PAL‐based target identification. A bioorthogonal sulfo‐click reaction was used to stably link a photocrosslinker unit with N‐acylsulfonamide linkage to produce a photoactivatable probe without any protection. In addition, the crosslinked protein was selectively isolated with a small cinnamate tag via linkage disruption upon N‐alkylation. Furthermore, the tag moiety was photochemically converted to a stable coumarin derivative by losing a water molecule, which is a useful property in MS‐based identification. 相似文献
8.
Dr. Jeffrey L. Gustafson Dr. Taavi K. Neklesa Carly S. Cox Dr. Anke G. Roth Dr. Dennis L. Buckley Dr. Hyun Seop Tae Dr. Thomas B. Sundberg D. Blake Stagg Dr. John Hines Prof. Donald P. McDonnell Dr. John D. Norris Prof. Craig M. Crews 《Angewandte Chemie (International ed. in English)》2015,54(33):9659-9662
9.
An Immucillin‐Based Transition‐State‐Analogous Inhibitor of tRNA–Guanine Transglycosylase (TGT) 下载免费PDF全文
Dr. Christoph Hohn Adrian Härtsch Frederik Rainer Ehrmann Dr. Toni Pfaffeneder Dr. Nils Trapp Dr. Oliver Dumele Prof. Dr. Gerhard Klebe Prof. Dr. François Diederich 《Chemistry (Weinheim an der Bergstrasse, Germany)》2016,22(20):6750-6754
Shigellosis is one of the most severe diarrheal diseases worldwide without any efficient treatment so far. The enzyme tRNA–guanine transglycosylase (TGT) has been identified as a promising target for small‐molecule drug design. Herein, we report a transition‐state analogue, a small, immucillin‐derived inhibitor, as a new lead structure with a novel mode of action. The complex inhibitor synthesis was accomplished in 18 steps with an overall yield of 3 %. A co‐crystal structure of the inhibitor bound to Z. mobilis TGT confirmed the predicted conformation of the immucillin derivative in the enzyme active site. 相似文献
10.
Dr. Gregory B. Craven Dr. Dominic P. Affron Dr. Charlotte E. Allen Dr. Stefan Matthies Dr. Joe G. Greener Dr. Rhodri M. L. Morgan Prof. Edward W. Tate Prof. Alan Armstrong Dr. David J. Mann 《Angewandte Chemie (International ed. in English)》2018,57(19):5257-5261
Cysteine‐reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high‐quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan‐reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine‐reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2‐selective allosteric (type IV) kinase inhibitor whose novel mode‐of‐action could be exploited therapeutically. 相似文献
11.
Rational Design and Identification of a Non‐Peptidic Aggregation Inhibitor of Amyloid‐β Based on a Pharmacophore Motif Obtained from cyclo[‐Lys‐Leu‐Val‐Phe‐Phe‐] 下载免费PDF全文
Tadamasa Arai Takushi Araya Dr. Daisuke Sasaki Dr. Atsuhiko Taniguchi Dr. Takeshi Sato Dr. Youhei Sohma Prof. Motomu Kanai 《Angewandte Chemie (International ed. in English)》2014,53(31):8236-8239
Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small‐molecule aggregation inhibitors of Alzheimer’s amyloid‐β (Aβ) are extremely scarce, however, and are mainly restricted to dye‐ and polyphenol‐type compounds that lack drug‐likeness. Based on the structure‐activity relationship of cyclic Aβ16–20 (cyclo‐[KLVFF]), we identified unique pharmacophore motifs comprising side‐chains of Leu2, Val3, Phe4, and Phe5 residues without involvement of the backbone amide bonds to inhibit Aβ aggregation. This finding allowed us to design non‐peptidic, small‐molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non‐peptidic, small‐molecule aggregation inhibitors of amyloids based on rational molecular design. 相似文献
12.
NMR Fingerprints of the Drug‐like Natural‐Product Space Identify Iotrochotazine A: A Chemical Probe to Study Parkinson’s Disease 下载免费PDF全文
Dr. Tanja Grkovic Dr. Rebecca H. Pouwer Marie‐Laure Vial Luca Gambini Alba Noël Dr. John N. A. Hooper Dr. Stephen A. Wood Dr. George D. Mellick Prof. Dr. Ronald J. Quinn 《Angewandte Chemie (International ed. in English)》2014,53(24):6070-6074
The NMR spectrum of a mixture of small molecules is a fingerprint of all of its components. Herein, we present an NMR fingerprint method that takes advantage of the fact that fractions contain simplified NMR profiles, with minimal signal overlap, to allow the identification of unique spectral patterns. The approach is exemplified in the identification of a novel natural product, iotrochotazine A ( 1 ), sourced from an Australian marine sponge Iotrochota sp. Compound 1 was used as a chemical probe in a phenotypic assay panel based on human olfactory neurosphere‐derived cells (hONS) from idiopathic Parkinson’s disease patients. Compound 1 at 1 μM was not cytotoxic but specifically affected the morphology and cellular distribution of lysosomes and early endosomes. 相似文献
13.
14.
Fragment‐Based De Novo Design Reveals a Small‐Molecule Inhibitor of Helicobacter Pylori HtrA 下载免费PDF全文
Thomas P. Schmidt Dr. Manja Böhm Katharina Stutz Daniel Reker Dr. Bernhard Pfeiffer Prof. Dr. Karl‐Heinz Altmann Prof. Dr. Steffen Backert Prof. Dr. Silja Wessler Prof. Dr. Gisbert Schneider 《Angewandte Chemie (International ed. in English)》2015,54(35):10244-10248
Sustained identification of innovative chemical entities is key for the success of chemical biology and drug discovery. We report the fragment‐based, computer‐assisted de novo design of a small molecule inhibiting Helicobacter pylori HtrA protease. Molecular binding of the designed compound to HtrA was confirmed through biophysical methods, supporting its functional activity in vitro. Hit expansion led to the identification of the currently best‐in‐class HtrA inhibitor. The results obtained reinforce the validity of ligand‐based de novo design and binding‐kinetics‐guided optimization for the efficient discovery of pioneering lead structures and prototyping drug‐like chemical probes with tailored bioactivity. 相似文献
15.
Yuanyuan Lin Jing Xu Qianqian Jia Wei Sun Jia Fu Yanni Lv Shengli Han 《Journal of separation science》2020,43(13):2571-2578
Mas‐related G protein‐coupled receptor X2 was a mast cell–specific receptor mediating anaphylactoid reactions by activating mast cells degranulation, and it was also identified as a target for modulating mast cell–mediated anaphylactoid and inflammatory diseases. The anti‐anaphylactoid drugs used clinically disturb the partial effect of partial mediators released by mast cells. The small molecule of Mas‐related G protein‐coupled receptor X2 specific antagonists may provide therapeutic action for the anaphylactoid and inflammatory diseases in the early stage. In this study, the Mas‐related G protein‐coupled receptor X2 high expression cell membrane chromatography was coupled online with liquid chromatography and mass spectrometry and successfully used to screen anti‐anaphylactoid components from Magnolia biondii Pamp. Fargesin and pinoresinol dimethyl ether were identified as potential anti‐anaphylactoid components. Bioactivity of these two components were investigated by β hexosaminidase and histamine release assays on mast cells, and it was found that these two components could inhibit β hexosaminidase and histamine release in a concentration‐dependent manner. This Mas‐related G protein‐coupled receptor X2 high expression cell membrane chromatography coupled online with liquid chromatography and mass spectrometry system could be applied for screening potential anti‐anaphylactoid components from natural medicinal herbs. This study also provided a powerful system for drug discovery in natural medicinal herbs. 相似文献
16.
David J.T. Hill Christopher M.L. Preston Andrew K. Whittaker Susan M. Hunt 《Macromolecular Symposia》2000,156(1):95-102
The radiation chemistry of poly(dimethyl siloxane) has been investigated with respect to identification of the nature of the small molecule chain scission products. Low molecular weight linear and cyclic products have been identified through the use of 29Si solution NMR, GPC and MALDI‐TOF mass spectrometry. It has been suggested that the low molecular weight cyclic products are formed by back‐biting depolymerization reactions. 相似文献
17.
A Small‐Molecule Protein–Protein Interaction Inhibitor of PARP1 That Targets Its BRCT Domain 下载免费PDF全文
Zhenkun Na Bo Peng Shukie Ng Sijun Pan Prof. Dr. Jun‐Seok Lee Prof. Dr. Han‐Ming Shen Prof. Dr. Shao Q. Yao 《Angewandte Chemie (International ed. in English)》2015,54(8):2515-2519
Poly(ADP‐ribose)polymerase‐1 (PARP1) is a BRCT‐containing enzyme (BRCT=BRCA1 C‐terminus) mainly involved in DNA repair and damage response and a validated target for cancer treatment. Small‐molecule inhibitors that target the PARP1 catalytic domain have been actively pursued as anticancer drugs, but are potentially problematic owing to a lack of selectivity. Compounds that are capable of disrupting protein–protein interactions of PARP1 provide an alternative by inhibiting its activities with improved selectivity profiles. Herein, by establishing a high‐throughput microplate‐based assay suitable for screening potential PPI inhibitors of the PARP1 BRCT domain, we have discovered that (±)‐gossypol, a natural product with a number of known biological activities, possesses novel PARP1 inhibitory activity both in vitro and in cancer cells and presumably acts through disruption of protein–protein interactions. As the first known cell‐permeable small‐molecule PPI inhibitor of PAPR1, we further established that (?)‐gossypol was likely the causative agent of PARP1 inhibition by promoting the formation of a 1:2 compound/PARP1 complex by reversible formation of a covalent imine linkage. 相似文献
18.
Mangesh A. Bangar Dhammanand J. Shirale Hemant J. Purohit Wilfred Chen Nosang V. Myung Ashok Mulchandani 《Electroanalysis》2011,23(2):371-379
We have fabricated a highly sensitive, simple and label‐free single polypyrrole (Ppy) nanowire based conductometric/chemiresistive DNA sensor. The fabrication was optimized in terms of probe DNA sequence immobilization using a linker molecule and using gold‐thiol interaction. Two resultant sensor designs working on two different sensing mechanisms (gating effect and work function based sensors) were tested to establish reliable sensor architecture with higher sensitivity and device‐to‐device reproducibility. The utility of the work function based configuration was demonstrated by detecting 19 base pair (bp) long breast cancer gene sequence with single nucleotide polymorphism (SNP) discrimination with high sensitivity, lower detection limit of ∼10−16 M and wide dynamic range (∼10−16 to 10−11 M) in a small sample volume (30 µL). To further demonstrate the utility of the DNA sensor for detection of target sequences with different number of bases, targets with 21 and 36 bases were detected. These sequences have implications in environmental sample analysis or metagenomics. Sensor response showed increase with the number of bases in the target sequence. For long sequence (with 36 bases), effect of DNA alignment on sensor performance was studied. 相似文献
19.
Eun Won Seo Ji Hee Han Cheol Ho Heo Prof. Dr. Jae Ho Shin Prof. Dr. Hwan Myung Kim Prof. Dr. Bong Rae Cho 《Chemistry (Weinheim an der Bergstrasse, Germany)》2012,18(39):12388-12394
Two‐photon microscopy (TPM) has become an indispensable tool in the study of biology and medicine due to the capability of this method for molecular imaging deep inside intact tissues. For the maximum utilization of TPM, a variety of two‐photon (TP) probes for specific applications are needed. In this article, we report a small‐molecule TP probe (ANO1) for nitric oxide (NO) that shows a rapid and specific NO response, a 68‐fold fluorescence enhancement in response to NO, and a maximum TP‐action cross‐section of 170 GM (GM: 10?50 cm4 photon?1) upon reaction with excess NO. This probe can be easily loaded into cells and tissues and can real‐time monitor NO in living tissues at 100–180 μm depth for longer than 1200 s through the use of TPM, with minimum interference from other biologically relevant species. 相似文献
20.
Xingxing Ge Xicheng Liu Zhenzhen Tian Shujiao Chen Xinyu Liu Lihua Guo Peiwei Gong Baoping Ling Xiang‐Ai Yuan Zhe Liu 《应用有机金属化学》2019,33(11)
Four half‐sandwich rutheniumII (RuII) complexes with triphenylamine‐modifed dipyridine frameworks were synthesized and characterized. The cytotoxicity of target complexes toward A549 (lung cancer cells), HeLa (cervical cancer cells) and HepG2 (hepatoma cells) were obtained by the MTT assay, which were superior to cisplatin with the IC50 values changed from 2.4 ± 0.1 μM to 9.2 ± 2.7 μM. Meanwhile, complexes possess the ability of antimetastasis to cancer cells. RuII complexes could be transported by serum albumin, catalyze the conversion of NADH (the reduced state of nicotinamide‐adenine dinucleotide) to NAD+ and induce the accumulation of reactive oxygen species, which confirmed the antineoplastic mechanism of oxidation. RuII complexes could enter A549 cells followed by a non‐energy dependent cellular uptake mechanism, target lysosomes with the Pearson's colocalization coefficient of 0.75, lead to lysosomal damage, disturb the cell cycle (S phase), and eventually induce apoptosis. The results demonstrate that these RuII complexes are potential anticancer agents with dual functions, including metastasis inhibition and lysosomal damage. 相似文献