keyword
MENU ▼
Read by QxMD icon Read
search

Covalent inhibitors

keyword
https://www.readbyqxmd.com/read/28091953/fullerene-c60-penetration-into-leukemic-cells-and-its-photoinduced-cytotoxic-effects
#1
D Franskevych, K Palyvoda, D Petukhov, S Prylutska, I Grynyuk, C Schuetze, L Drobot, O Matyshevska, U Ritter
Fullerene C60 as a representative of carbon nanocompounds is suggested to be promising agent for application in photodynamic therapy due to its unique physicochemical properties. The goal of this study was to estimate the accumulation of fullerene C60 in leukemic cells and to investigate its phototoxic effect on parental and resistant to cisplatin leukemic cells. Stable homogeneous water colloid solution of pristine C60 with average 50-nm diameter of nanoparticles was used in experiments. Fluorescent labeled C60 was synthesized by covalent conjugation of C60 with rhodamine B isothiocyanate...
December 2017: Nanoscale Research Letters
https://www.readbyqxmd.com/read/28088021/sanguinarine-induced-oxidative-stress-and-apoptosis-like-programmed-cell-death-al-pcd-in-root-meristem-cells-of-allium-cepa
#2
Aneta Żabka, Konrad Winnicki, Justyna Teresa Polit, Janusz Maszewski
A vast number of studies on plant cell systems clearly indicate that various biotic and abiotic stresses give rise to the uncontrolled increase in the level of reactive oxygen species (ROS). Excess concentrations of ROS result in damage to proteins, lipids, carbohydrates, and DNA, which may lead, in consequence, to the apoptotic cell death. The current study investigates the effects of sanguinarine (SAN), a natural alkaloid derived from the roots of Sanguinaria canadensis, on root apical meristem cells of Allium cepa...
January 4, 2017: Plant Physiology and Biochemistry: PPB
https://www.readbyqxmd.com/read/28087320/poly-adp-ribose-polymerase-activity-and-inhibition-in-cancer
#3
REVIEW
Caleb Dulaney, Samuel Marcrom, Jennifer Stanley, Eddy S Yang
Genomic instability resultant from defective DNA repair mechanisms is a fundamental hallmark of cancer. The poly(ADP-ribose) polymerase (PARP) proteins 1, 2 and 3 catalyze the polymerization of poly(ADP-ribose) and covalent attachment to proteins in a phylogenetically ancient form of protein modification. PARPs play a role in base excision repair, homologous recombination, and non-homologous end joining. The discovery that loss of PARP activity had cytotoxic effects in cells deficient in homologous recombination has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP inhibitor for clinical use in patients with ovarian cancer and defective homologous recombination...
January 10, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/28079302/molecular-basis-for-covalent-inhibition-of-glyceraldehyde-3-phosphate-dehydrogenase-by-a-2-phenoxy-1-4-naphthoquinone-small-molecule
#4
Stefano Bruno, Elisa Uliassi, Mirko Zaffagnini, Federica Prati, Christian Bergamini, Riccardo Amorati, Gianluca Paredi, Marilena Margiotta, Paola Conti, Maria Paola Costi, Marcel Kaiser, Andrea Cavalli, Romana Fato, Maria Laura Bolognesi
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has recently gained attention as an anti-protozoan and anti-cancer drug target. We have previously identified 2-phenoxy-1,4-naphthoquinone as an inhibitor of both Trypanosoma brucei and human GAPDH. Herein, through multiple chemical, biochemical, and biological studies, and through the design of analogs, we confirmed the formation of a covalent adduct, we clarified the inhibition mechanism and we demonstrated antitrypanosomal, antiplasmodial and cytotoxic activities in cell cultures...
January 12, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28075527/recent-development-of-the-second-and-third-generation-irreversible-egfr-inhibitors
#5
REVIEW
Weiwei Han, Yongli Du
Recent reports suggested that essential directions for new lung cancer, breast carcinoma therapies, as well as the roomier realm of targeted cancer therapies were provided through targeting the epidermal growth factor receptor (EGFR). Patients who carrying non-small cell lung carcinoma (NSCLC) with activating mutations in EGFR initially respond well to the EGFR inhibitors erlotinib and gefitinib, which were located the active site of the EGFR kinase and designed to act as competitive inhibitors of combining with the ATP...
January 11, 2017: Chemistry & Biodiversity
https://www.readbyqxmd.com/read/28074489/a-novel-nf-%C3%AE%C2%BAb-inhibitor-edasalonexent-cat-1004-in-development-as-a-disease-modifying-treatment-for-patients-with-duchenne-muscular-dystrophy-phase-1-safety-pharmacokinetics-and-pharmacodynamics-in-adult-subjects
#6
Joanne M Donovan, Michael Zimmer, Elliot Offman, Toni Grant, Michael Jirousek
In Duchenne muscular dystrophy (DMD), NF-κB is activated in skeletal muscle from infancy regardless of the underlying dystrophin mutation and drives inflammation and muscle degeneration while inhibiting muscle regeneration. Edasalonexent (CAT-1004) is a bifunctional orally administered small molecule that covalently links 2 compounds known to inhibit NF-κB, salicylic acid and docosahexaenoic acid (DHA). Edasalonexent is designed to inhibit activated NF-κB upon intracellular cleavage to these bioactive components...
January 11, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28070909/peptide-fibrils-as-monomer-storage-of-the-covalent-hiv-1-integrase-inhibitor
#7
Koushik Chandra, Priyadip Das, Norman Metanis, Assaf Friedler, Meital Reches
We have recently reported the covalent inhibition of HIV-1 integrase by an N-terminal succinimide-modified lens epithelium-derived growth factor (361-370) peptide. We also showed that this peptide is proteolytically stable. Here, we show that this inhibitor is stored as fibrils that serve as a stock for the inhibitory monomers. The fibrils increase the local concentration of the peptide at the target protein. When the monomers bind integrase, the equilibrium between the fibrils and their monomers shifts towards the formation of peptide monomers...
January 10, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/28067849/pnserpin-a-novel-serine-protease-inhibitor-from-extremophile-pyrobaculum-neutrophilum
#8
Huan Zhang, Rui Fei, Baigong Xue, Shanshan Yu, Zuoming Zhang, Sheng Zhong, Yuanqi Gao, Xiaoli Zhou
Serine protease inhibitors (serpins) are native inhibitors of serine proteases, constituting a large protein family with members spread over eukaryotes and prokaryotes. However, only very few prokaryotic serpins, especially from extremophiles, have been characterized to date. In this study, Pnserpin, a putative serine protease inhibitor from the thermophile Pyrobaculum neutrophilum, was overexpressed in Escherichia coli for purification and characterization. It irreversibly inhibits chymotrypsin-, trypsin-, elastase-, and subtilisin-like proteases in a temperature range from 20 to 100 °C in a concentration-dependent manner...
January 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28064083/identification-of-novel-pad4-inhibitors-based-on-a-pharmacophore-model-derived-from-transition-state-coordinates
#9
Yu Wei, Ruihua Liu, Cui Liu, Jin Jin, Dongmei Li, Jianping Lin
1.4 Protein arginine deiminases 4 (PAD4) is an attractive target for the development of novel and selective inhibitors of Rheumatoid Arthritis (RA). F-amidine is known as mechanism-based inhibitor targeting PAD4 and used as inactivators by covalently modifying the active site Cys645. To identify novel structural inhibitors of PAD4, we investigated the flexibility of protein on basis of the transition state geometry of PAD4 inhibited by F-amidine from our previous QM/MM calculation. And a pharmacophore model was generated containing four features (ADHH) using five representative structures from molecular dynamic (MD) simulation on basis of the transition state geometry of PAD4 inhibited by F-amidine...
December 19, 2016: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28063993/inhibition-of-enterovirus-71-replication-by-an-%C3%AE-hydroxy-nitrile-derivative-nk-1-9k
#10
Yaxin Wang, Lin Cao, Yangyang Zhai, Jiaming Ma, Quandeng Nie, Ting Li, Zheng Yin, Yuna Sun, Luqing Shang
Enterovirus 71 (EV71) is one of the major etiological agents of human hand-foot-and-mouth disease (HFMD) worldwide. EV71 infection in young children and people with immunodeficiency causes severe symptoms with a high fatality rates. However, there is still no approved drugs to treat such infections. Based on our previous report of a peptide-aldehyde anti-EV71 protease, we present here a highly specific α-hydroxy-nitrile derivative NK-1.9k, which inhibited the proliferation of multiple EV71 strains and coxsackievirus A16 (CVA16) in various cells with EC50 of 37...
January 4, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28063825/impact-of-mutations-on-the-higher-order-structure-and-activity-of-a-recombinant-uricase
#11
Flaviu Gruia, Arun Parupudi, Manuel Baca, Chris Ward, Andrew Nyborg, Richard L Remmele, Jared S Bee
This study explores the structural and functional changes associated with a low temperature thermal transition of two engineered bacterial uricase mutants. Uricase has a non-covalent homo-tetrameric structure, with four active sites located at the interface of subunits. Using differential scanning calorimetry, a low temperature transition was identified at 42ºC for mutant A and at 33°C for mutant B. This transition was stabilized by the uricase inhibitor, oxonic acid, suggesting a strong structural relationship to the active site...
January 4, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28063351/novel-4-4-substituted-amidobenzyl-furan-2-5h-one-derivatives-as-topoisomerase-i-inhibitors
#12
Cheng-Kang Peng, Ting Zeng, Xing-Jun Xu, Yi-Qun Chang, Wen Hou, Kuo Lu, Hui Lin, Ping-Hua Sun, Jing Lin, Wei-Min Chen
In this study, two series of novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives containing an α,β-unsaturated lactone fragment were synthesized and screened for Topo I inhibition and antitumor activity. The topoisomerase I inhibitory activities and cytotoxicities against three human cancer cell lines (MCF-7,Hela,A549) were evaluated. The results revealed that series 2, compounds bearing an exocyclic double bond on the furanone ring, generally showed more potent activity than series 1, compounds lacking an exocyclic double bond...
December 20, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28062113/indirect-treatment-comparisons-of-ibrutinib-versus-physician-s-choice-and-idelalisib-plus-ofatumumab-in-patients-with-previously-treated-chronic-lymphocytic-leukemia
#13
REVIEW
Sonja Sorensen, Mark Wildgust, Nishan Sengupta, Cristina Trambitas, Joris Diels, Suzy van Sanden, Yingxin Xu, Emily Dorman
PURPOSE: Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0...
January 3, 2017: Clinical Therapeutics
https://www.readbyqxmd.com/read/28060514/targeted-covalent-inhibition-of-grb2-sos1-interaction-through-proximity-induced-conjugation-in-breast-cancer-cells
#14
Yongsheng Yu, Yunyu Nie, Qian Feng, Jiale Qu, Rui Wang, Liming Bian, Jiang Xia
Targeted covalent inhibitors of protein-protein interactions differ from reversible inhibitors in that the former bind and covalently bond the target protein at a specific site of the target. The site specificity is the result of the proximity of two reactive groups at the bound state, for example one mild electrophile in the inhibitor and a natural cysteine in the target close to the ligand binding site. Only a few pharmaceutically relevant proteins have this structural feature. Grb2, a key adaptor protein in maintaining the ERK activity via binding Sos1 to activated RTKs, is one: the N-terminal SH3 domain of Grb2 (Grb2N-SH3) carries a unique solvent-accessible cysteine Cys32 close to its Sos1-binding site...
January 6, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28059487/%C3%AE-tocopheryl-phosphate-induces-vegf-expression-via-cd36-pi3k%C3%AE-in-thp-1-monocytes
#15
Jean-Marc Zingg, Angelo Azzi, Mohsen Meydani
The CD36 scavenger receptor binds several ligands and mediates ligand uptake and ligand-dependent signal transduction and gene expression, events that may involve CD36 internalization. Here we show that CD36 internalization in THP-1 monocytes is triggered by α-tocopherol (αT) and more strongly by α-tocopheryl phosphate (αTP) and EPC-K1, a phosphate diester of αTP and L-ascorbic acid. αTP-triggered CD36 internalization is prevented by the specific covalent inhibitor of selective lipid transport by CD36, sulfo-N-succinimidyl oleate (SSO)...
January 6, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/28058282/protein-degradation-by-in-cell-self-assembly-of-proteolysis-targeting-chimeras
#16
Honorine Lebraud, David J Wright, Christopher N Johnson, Tom D Heightman
Selective degradation of proteins by proteolysis targeting chimeras (PROTACs) offers a promising potential alternative to protein inhibition for therapeutic intervention. Current PROTAC molecules incorporate a ligand for the target protein, a linker, and an E3 ubiquitin ligase recruiting group, which bring together target protein and ubiquitinating machinery. Such hetero-bifunctional molecules require significant linker optimization and possess high molecular weight, which can limit cellular permeation, solubility, and other drug-like properties...
December 28, 2016: ACS Central Science
https://www.readbyqxmd.com/read/28053672/serotonin-improves-glucose-metabolism-by-serotonylation-of-the-small-gtpase-rab4-in-l6-skeletal-muscle-cells
#17
Ramona Al-Zoairy, Michael T Pedrini, Mohammad Imran Khan, Julia Engl, Alexander Tschoner, Christoph Ebenbichler, Gerhard Gstraunthaler, Karin Salzmann, Rania Bakry, Andreas Niederwanger
BACKGROUND: Serotonin (5-HT) improves insulin sensitivity and glucose metabolism, however, the underlying molecular mechanism has remained elusive. Previous studies suggest that 5-HT can activate intracellular small GTPases directly by covalent binding, a process termed serotonylation. Activated small GTPases have been associated with increased GLUT4 translocation to the cell membrane. Therefore, we investigated whether serotonylation of small GTPases may be involved in improving Insulin sensitivity and glucose metabolism...
2017: Diabetology & Metabolic Syndrome
https://www.readbyqxmd.com/read/28051857/broad-spectrum-kinase-profiling-in-live-cells-with-lysine-targeted-sulfonyl-fluoride-probes
#18
Qian Zhao, Xiaohu Ouyang, Xiaobo Wan, Ketan S Gajiwala, John C Kath, Lyn H Jones, Alma L Burlingame, Jack Taunton
Protein kinases comprise a large family of structurally related enzymes. A major goal in kinase-inhibitor development is to selectively engage the desired kinase while avoiding myriad off-target kinases. However, quantifying inhibitor interactions with multiple endogenous kinases in live cells remains an unmet challenge. Here, we report the design of sulfonyl fluoride probes that covalently label a broad swath of the intracellular kinome with high efficiency. Protein crystallography and mass spectrometry confirmed a chemoselective reaction between the sulfonyl fluoride and a conserved lysine in the ATP binding site...
January 4, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28049654/histone-lysine-demethylase-inhibitors
#19
REVIEW
Ashwini Jambhekar, Jamie N Anastas, Yang Shi
The dynamic regulation of covalent modifications to histones is essential for maintaining genomic integrity and cell identity and is often compromised in cancer. Aberrant expression of histone lysine demethylases has been documented in many types of blood and solid tumors, and thus demethylases represent promising therapeutic targets. Recent advances in high-throughput chemical screening, structure-based drug design, and structure-activity relationship studies have improved both the specificity and the in vivo efficacy of demethylase inhibitors...
January 3, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28039278/inhibition-of-%C3%AE-lactamases-of-mycobacteria-by-avibactam-and-clavulanate
#20
Daria Soroka, Clément Ourghanlian, Fabrice Compain, Marion Fichini, Vincent Dubée, Jean-Luc Mainardi, Jean-Emmanuel Hugonnet, Michel Arthur
OBJECTIVES: Mycobacterium tuberculosis and Mycobacterium abscessus produce broad-spectrum class A β-lactamases, BlaC and BlaMab, which are inhibited by clavulanate and avibactam, respectively. BlaC differs from BlaMab at Ambler position 132 in the conserved motif SDN (SDG versus SDN, respectively). Here, we investigated whether this polymorphism could account for the inhibition specificity of β-lactamases from slowly and rapidly growing mycobacteria. METHODS: Enzyme kinetics were determined to assess the impact of the substitutions G(132)N in BlaC and N(132)G in BlaMab on β-lactamase inhibition by clavulanate and avibactam...
December 30, 2016: Journal of Antimicrobial Chemotherapy
keyword
keyword
89350
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"