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Covalent inhibitors

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https://www.readbyqxmd.com/read/28723089/a-new-class-of-glycoside-hydrolase-mechanism-based-covalent-inhibitors-glycosylation-transition-state-conformations
#1
Saeideh Shamsi Kazem Abadi, Michael Tran, Anuj Yadav, Pal John Pal Adabala, Saswati Chakladar, Andrew J Bennet
The design of covalent inhibitors in glycoscience research is important for the development of chemical biology probes. Here we report the synthesis of a new carbocyclic mechanism-based covalent inhibitor of an α-glucosidase. The enzyme efficiently catalyzes its alkylation via either an allylic cation or a cationic transition state. We show that this allylic covalent inhibitor has very different catalytic proficiencies for pseudo-glycosylation and deglycosylation. Such inhibitors have the potential to be useful chemical biology tools...
July 19, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28718624/covalent-enzyme-inhibition-through-fluorosulfate-modification-of-a-non-catalytic-serine-residue
#2
Olugbeminiyi O Fadeyi, Lise R Hoth, Chulho Choi, Xidong Feng, Ariamala Gopalsamy, Erik C Hett, Robert E Kyne, Ralph P Robinson, Lyn H Jones
Irreversible enzyme inhibitors often utilize the reaction of a protein cysteine residue with an appropriately positioned electrophile (an acrylamide for example) in the ligand template. Cysteine residues are not always available for site-specific protein labeling and therefore new approaches are needed to expand the toolkit of appropriate electrophiles that target alternative amino acids. We have previously described the rational targeting of tyrosine residues in the active site of a protein (the mRNA decapping scavenger enzyme, DcpS) using inhibitors armed with sulfonyl fluoride electrophiles that additionally enabled the subsequent development of clickable probe technology to measure drug-target occupancy in live cells...
July 18, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28715001/structural-evidence-for-the-covalent-modification-of-fabh-by-4-5-dichloro-1-2-dithiol-3-one-hr45
#3
Alexander G Ekström, Van Kelly, Jon Marles-Wright, Scott L Cockroft, Dominic J Campopiano
We use mass spectrometry analysis and molecular modelling to show the established antimicrobial inhibitor 4,5-dichloro-1,2-dithiol-3-one (HR45) acts by forming a covalent adduct with the target β-ketoacyl-ACP synthase III (FabH). The 5-chloro substituent directs attack of the essential active site thiol (C112) via a Michael-type addition elimination reaction mechanism.
July 17, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28710962/discovery-of-potent-molecular-chimera-cm358-to-treat-human-metastatic-melanoma
#4
Y Gilad, H Tuchinsky, G Ben-David, R Minnes, A Gancz, H Senderowitz, G Luboshits, M A Firer, G Gellerman
The resistance of cancer cells to chemotherapeutic agents, whether through intrinsic mechanisms or developed resistance, motivates the search for new chemotherapeutic strategies. In the present report, we demonstrate a facile synthetic strategy towards the discovery of new anti-cancer substances. This strategy is based on simple covalent coupling between known anti-cancer drugs, which results in novel 'chimeric' small molecules. One of these novel compounds, CM358, is the product of an amide bond formation between the known Topoisomerase II (Topo II) inhibitor amonafide (AM) and the known DNA mustard alkylator chlorambucil (CLB)...
June 29, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28709952/potent-inhibitors-of-human-lat1-slc7a5-transporter-based-on-dithiazole-and-dithiazine-compounds-for-development-of-anticancer-drugs
#5
Lara Napolitano, Mariafrancesca Scalise, Maria Koyioni, Panayotis Koutentis, Marco Catto, Ivano Eberini, Chiara Parravicini, Luca Palazzolo, Leonardo Pisani, Michele Galluccio, Lara Console, Angelo Carotti, Cesare Indiveri
The LAT1 transporter is acknowledged as a pharmacological target of tumours since it is strongly overexpressed in many human cancers. The purpose of this work was to find novel compounds exhibiting potent and prolonged inhibition of the transporter. To this aim, compounds based on dithiazole and dithiazine scaffold have been screened in the proteoliposome experimental model. Inhibition was tested on the antiport catalysed by hLAT1 as transport of extraliposomal [(3)H]histidine in exchange with intraliposomal histidine...
July 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28709638/dna-methylation-protects-against-cisplatin-induced-kidney-injury-by-regulating-specific-genes-including-interferon-regulatory-factor-8
#6
Chunyuan Guo, Lirong Pei, Xiao Xiao, Qingqing Wei, Jian-Kang Chen, Han-Fei Ding, Shuang Huang, Guoping Fan, Huidong Shi, Zheng Dong
DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals...
July 11, 2017: Kidney International
https://www.readbyqxmd.com/read/28706291/structural-and-functional-characterization-of-a-darpin-which-inhibits-ras-nucleotide-exchange
#7
Sandrine Guillard, Paulina Kolasinska-Zwierz, Judit Debreczeni, Jason Breed, Jing Zhang, Nicolas Bery, Rose Marwood, Jon Tart, Ross Overman, Pawel Stocki, Bina Mistry, Christopher Phillips, Terence Rabbitts, Ronald Jackson, Ralph Minter
Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a Kd of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells...
July 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/28698228/perturbations-to-lysyl-oxidase-expression-broadly-influence-the-transcriptome-of-lung-fibroblasts
#8
Ivana Mižíková, Francesco Palumbo, Tamás Tábi, Susanne Herold, István Vadász, Konstantin Mayer, Werner Seeger, Rory E Morty
Lysyl oxidases are credited with pathogenic roles in lung diseases, including cancer, fibrosis, pulmonary hypertension, congenital diaphragmatic hernia, and bronchopulmonary dysplasia (BPD). Lysyl oxidases facilitate the covalent intra- and inter-molecular cross-linking of collagen and elastin fibers, thereby imparting tensile strength to the extracellular matrix (ECM). Alternative ECM-independent roles have recently been proposed for lysyl oxidases, including regulation of growth factor signaling, chromatin remodeling, and transcriptional regulation; all of which impact cell phenotype...
July 10, 2017: Physiological Genomics
https://www.readbyqxmd.com/read/28697309/identification-of-natural-products-that-inhibit-the-catalytic-function-of-human-tyrosyl-dna-phosphodiesterase-tdp1
#9
Alun Bermingham, Edmund Price, Christophe Marchand, Adel Chergui, Alena Naumova, Emily L Whitson, Lauren R H Krumpe, Ekaterina I Goncharova, Jason R Evans, Tawnya C McKee, Curtis J Henrich, Yves Pommier, Barry R O'Keefe
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme crucial for cleavage of the covalent topoisomerase 1-DNA complex, an intermediate in DNA repair. TDP1 plays a role in reversing inhibition of topoisomerase I by camptothecins, a series of potent and effective inhibitors used in the treatment of colorectal, ovarian, and small-cell lung cancers. It is hypothesized that inhibition of TDP1 activity may enhance camptothecin sensitivity in tumors. Here, we describe the design, development, and execution of a novel assay to identify inhibitors of TDP1 present in natural product extracts...
July 1, 2017: SLAS Discovery
https://www.readbyqxmd.com/read/28696694/discovery-of-potent-small-molecule-inhibitors-of-ubiquitin-conjugating-enzyme-ubch5c-from-%C3%AE-santonin-derivatives
#10
Hao Chen, Guozhen Wu, Shuang Gao, Ruihua Guo, Zeng Zhao, Hu Yuan, Shanxiang Liu, Jian Wu, Xiaolong Lu, Xing Yuan, Zongmin Yu, Xianpeng Zu, Ning Xie, Niao Yang, Zhenlin Hu, Qingyan Sun, Weidong Zhang
As a therapeutic target for anti-tumor necrosis factor (TNF)-α interventions, UbcH5c is one of the key ubiquitin-conjugating enzymes catalyzing ubiquitination during TNF-α-triggered nuclear factor kappa B (NF-κB) activation. In the present study, three series of analogs were designed and synthesized from α-santonin, and their UbcH5c inhibitory activities were screened by western blotting and NF-κB luciferase assay. Further BIAcore, in-gel fluorescence imaging and immunoprecipitation, assays demonstrated that compound 6d exhibited robust and specific inhibition of UbcH5c, exceeding that of the positive compound 1 (IJ-5)...
July 11, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28696179/insights-into-the-crystal-structure-of-brd2-bd2-phenanthridinone-complex-and-theoretical-studies-on-phenanthridinone-analogs
#11
Shruti Mathur, Prashant Deshmukh, Shailesh Tripathi, Palaniappan Marimuthu, Balasundaram Padmanbhan
BET (Bromodomain and Extra-terminal) family proteins recognize the acetylated histone code on chromatin and participate in downstream processes like DNA replication, modification, and repair. As part of epigenetic approaches, BRD2 and BRD4 were identified as putative targets, for the management of chronic diseases. We have recently reported the discovery of a new scaffold of the phenanthridinone based inhibitor (L10) of the second bromodomain of BRD2 (BRD2-BD2). Here, we present the crystal structure of the BRD2-BD2, refined to 1...
July 11, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28695300/new-fty720-docetaxel-nanoparticle-therapy-overcomes-fty720-induced-lymphopenia-and-inhibits-metastatic-breast-tumour-growth
#12
Heba Alshaker, Qi Wang, Shyam Srivats, Yimin Chao, Colin Cooper, Dmitri Pchejetski
PURPOSE: Combining molecular therapies with chemotherapy may offer an improved clinical outcome for chemoresistant tumours. Sphingosine-1-phosphate (S1P) receptor antagonist and sphingosine kinase 1 (SK1) inhibitor FTY720 (FTY) has promising anticancer properties, however, it causes systemic lymphopenia which impairs its use in cancer patients. In this study, we developed a nanoparticle (NP) combining docetaxel (DTX) and FTY for enhanced anticancer effect, targeted tumour delivery and reduced systemic toxicity...
July 10, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28689970/structural-dynamics-of-zika-virus-ns2b-ns3-protease-binding-to-dipeptide-inhibitors
#13
Yan Li, Zhenzhen Zhang, Wint Wint Phoo, Ying Ru Loh, Weiling Wang, Shuang Liu, Ming Wei Chen, Alvin W Hung, Thomas H Keller, Dahai Luo, CongBao Kang
The NS2B-NS3 viral protease is an attractive drug target against Zika virus (ZIKV) due to its importance in viral replication and maturation. Here we report the crystal structure of protease in complex with a dipeptide inhibitor, Acyl-KR-aldehyde (compound 1). The aldehyde moiety forms a covalent bond with the catalytic Ser(135) of NS3. The Arg and Lys residues in the inhibitor occupy the S1 and S2 sites of the protease, respectively. Nuclear magnetic resonance studies demonstrate that the complex is in the closed conformation in solution...
June 23, 2017: Structure
https://www.readbyqxmd.com/read/28689404/discovery-of-a-covalent-kinase-inhibitor-from-a-dna-encoded-small-molecule-library-x-protein-library-selection
#14
Alix I Chan, Lynn M McGregor, Tara Jain, David R Liu
We previously reported interaction determination using unpurified proteins (IDUP), a method to selectively amplify DNA sequences encoding ligand:target pairs from a mixture of DNA-linked small molecules and unpurified protein targets in cell lysates. In this study we applied IDUP to libraries of DNA-encoded bioactive compounds and DNA-tagged human kinases to identify ligand:protein binding partners out of 32,096 possible combinations in a single solution-phase library × library experiment. The results recapitulated known small molecule:protein interactions and also revealed that ethacrynic acid is a novel ligand and inhibitor of MAP2K6 kinase...
July 9, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28687272/interstrand-crosslink-repair-as-a-target-for-hdac-inhibition
#15
REVIEW
Teodora Nikolova, Nicole Kiweler, Oliver H Krämer
DNA interstrand crosslinks (ICLs) covalently connect complementary DNA strands. Consequently, DNA replication and transcription are hampered, DNA damage responses (DDR) are initiated, and cell death is triggered. Therefore, drugs inducing ICLs are effective against rapidly growing cancer cells. However, tumors engage a complicated enzymatic machinery to repair and survive ICLs. Several factors, including the post-translational acetylation/deacetylation of lysine residues within proteins, control this network...
July 4, 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28684316/regulation-of-calcium-release-from-the-endoplasmic-reticulum-by-the-serine-hydrolase-abhd2
#16
Bogeon Yun, HeeJung Lee, Roger Powell, Nichole Reisdorph, Heather Ewing, Michael H Gelb, Ku-Lung Hsu, Benjamin F Cravatt, Christina C Leslie
The serine hydrolase inhibitors pyrrophenone and KT195 inhibit cell death induced by A23187 and H2O2 by blocking the release of calcium from the endoplasmic reticulum and mitochondrial calcium uptake. The effect of pyrrophenone and KT195 on these processes is not due to inhibition of their known targets, cytosolic phospholipase A2 and α/β-hydrolase domain-containing (ABHD) 6, respectively, but represent off-target effects. To identify targets of KT195, fibroblasts were treated with KT195-alkyne to covalently label protein targets followed by click chemistry with biotin azide, enrichment on streptavidin beads and tryptic peptide analysis by mass spectrometry...
July 3, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28683919/sortase-transpeptidases-structural-biology-and-catalytic-mechanism
#17
Alex W Jacobitz, Michele D Kattke, Jeff Wereszczynski, Robert T Clubb
Gram-positive bacteria use sortase cysteine transpeptidase enzymes to covalently attach proteins to their cell wall and to assemble pili. In pathogenic bacteria sortases are potential drug targets, as many of the proteins that they display on the microbial surface play key roles in the infection process. Moreover, the Staphylococcus aureus Sortase A (SaSrtA) enzyme has been developed into a valuable biochemical reagent because of its ability to ligate biomolecules together in vitro via a covalent peptide bond...
2017: Advances in Protein Chemistry and Structural Biology
https://www.readbyqxmd.com/read/28683197/immobilization-strategies-for-functional-complement-convertase-assembly-at-lipid-membrane-interfaces
#18
Saziye Yorulmaz Avsar, Joshua Alexander Jackman, Min Chul Kim, Bo Kyeong Yoon, Walter Hunziker, Nam-Joon Cho
The self-assembly formation of complement convertases - essential biomacromolecular complexes which amplify innate immune responses - is triggered by protein adsorption. Herein, a supported lipid bilayer platform was utilized in order to investigate the effects of covalent and noncovalent tethering strategies on the self-assembly of alternative pathway C3 convertase components, starting with C3b protein adsorption followed by addition of factors B and D. Quartz crystal microbalance-dissipation (QCM-D) experiments measured the real-time kinetics of convertase assembly onto supported lipid bilayers...
July 6, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
https://www.readbyqxmd.com/read/28682613/synthesis-of-a-3-amino-2-3-dihydropyrid-4-one-and-related-heterocyclic-analogs-as-mechanism-based-inhibitors-of-bioa-a-pyridoxal-phosphate-plp-dependent-enzyme
#19
Carter G Eiden, Courtney C Aldrich
Amiclenomycin (ACM) is a chemically unstable antibiotic with selective activity against Mycobacterium tuberculosis (Mtb) due to mechanism-based inhibition of BioA, a pyridoxal 5'-phosphate (PLP) dependent aminotransferase that catalyzes the second step of biotin biosynthesis. The first-generation ACM analogue dihydro-2-pyridone 1 is semi-stable and maintains a similar bioactivation mechanism concluding with covalent labeling of the PLP cofactor. To improve on 1, we report the synthesis of dihydro-4-pyranone 2, dihydro-4-pyridone 3 and dihydro-4-thiopyranone 13...
July 6, 2017: Journal of Organic Chemistry
https://www.readbyqxmd.com/read/28675039/structural-insights-into-substrate-specificity-of-cystathionine-%C3%AE-synthase-from-corynebacterium-glutamicum
#20
Hye-Young Sagong, Kyung-Jin Kim
Cystathionine γ-synthase (MetB) condenses O-acetyl-l-homoserine (OAHS) or O-succinyl-l-homoserine (OSHS) with cysteine to produce cystathionine. To investigate the molecular mechanisms and substrate specificity of MetB from Corynebacterium glutamicum (CgMetB), we determined its crystal structure at 1.5 Å resolution. The pyridoxal phosphate cofactor is covalently bound to Lys204 via a Schiff base linkage in the deep cavity. Superposition with the structure of MetB from Nicotiana tabacum in complex with its inhibitor dl-(E)-2-amino-5-phosphono-3-pentenoic acid revealed that Thr347 from the β10-β11 connecting loop, located at the entrance of the active site, is speculated to be a main contributor for stabilization of the acetyl group of OAHS...
July 13, 2017: Journal of Agricultural and Food Chemistry
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