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Covalent inhibitors

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https://www.readbyqxmd.com/read/28544013/-epigallocatechin-3-gallate-inhibits-human-angiotensin-converting-enzyme-activity-through-an-autoxidation-dependent-mechanism
#1
Zhe Liu, Sayaka Nakashima, Toshiyuki Nakamura, Shintaro Munemasa, Yoshiyuki Murata, Yoshimasa Nakamura
We investigated the molecular mechanisms involved in the angiotensin-converting enzyme (ACE) inhibition by (-)-epigallocatechin-3-gallate (EGCg), a major tea catechin. EGCg inhibited both the ACE activity in the lysate of human colorectal cancer cells and human recombinant ACE (rh-ACE) in a dose-dependent manner. Co-incubation with zinc sulfate showed no influence on the rh-ACE inhibition by EGCg, whereas it completely counteracted the inhibitory effect of ethylenediaminetetraacetic acid, a chelating-type ACE inhibitor...
May 23, 2017: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/28534914/covalent-inhibition-of-protein-tyrosine-phosphatases
#2
REVIEW
Kasi Viswanatharaju Ruddraraju, Zhong-Yin Zhang
Protein tyrosine phosphatases (PTPs) are a large family of 107 signaling enzymes that catalyze the hydrolytic removal of phosphate groups from tyrosine residues in a target protein. The phosphorylation status of tyrosine residues on proteins serve as a ubiquitous mechanism for cellular signal transduction. Aberrant function of PTPs can lead to many human diseases, such as diabetes, obesity, cancer, and autoimmune diseases. As the number of disease relevant PTPs increases, there is urgency in developing highly potent inhibitors that are selective towards specific PTPs...
May 23, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28532685/nitroxide-4-hydroxy-2-2-6-6-tetramethylpiperidine-1-oxyl-tempol-inhibits-the-reductase-activity-of-protein-disulfide-isomerase-via-covalent-binding-to-the-cys400-residue-on-cxxc-redox-motif-at-the-a-active-site
#3
Gérsika Bitencourt Santos, Lucia Gonzalez-Perilli, Mauricio Mastrogiovanni, Adrián Aicardo, Cláudio Daniel Cerdeira, Andrés Trostchansky, Maísa Ribeiro Pereira Lima Brigagão
BACKGROUND AND AIM: Oxidative stress arising from inflammatory processes is a serious cause of cell and tissue damage. Tempol is an efficient antioxidant with superoxide dismutase-like activity. The purpose of this paper is to address the inhibition of protein disulfide isomerase (PDI), an essential redox chaperone whose active sites contain the Cys-Gly-His-Cys (CXXC) motif, by the nitroxide Tempol. RESULTS: In the presence of Tempol (5-120 μM), the reductase activity of PDI was reversibly affected both in vitro and in activated mice neutrophils, with an IC50 of 22...
May 19, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28530791/farnesyltransferase-mediated-delivery-of-a-covalent-inhibitor-overcomes-alternative-prenylation-to-mislocalize-k-ras
#4
Christopher J Novotny, Gregory L Hamilton, Frank McCormick, Kevan Shokat
Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of farnesyltransferase inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition though alternative prenylation by geranylgeranyltransferase...
May 22, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28528876/modeling-covalent-modifier-drugs
#5
REVIEW
Ernest Awoonor-Williams, Andrew G Walsh, Christopher N Rowley
In this review, we present a summary of how computer modeling has been used in the development of covalent modifier drugs. Covalent modifier drugs bind by forming a chemical bond with their target. This covalent binding can improve the selectivity of the drug for a target with complementary reactivity and result in increased binding affinities due to the strength of the covalent bond formed. In some cases, this results in irreversible inhibition of the target, but some targeted covalent inhibitor (TCI) drugs bind covalently but reversibly...
May 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28521657/several-inhibitors-of-the-plk1-polo-box-domain-turn-out-to-be-non-specific-protein-alkylators
#6
Vincent Archambault, Karine Normandin
For almost a decade, there has been much interest in the development of chemical inhibitors of Polo-like kinase 1 (Plk1) protein interactions. Plk1 is a master regulator of the cell division cycle that controls numerous substrates. It is a promising target for cancer drug development. Inhibitors of the kinase domain of Plk1 had some success in clinical trials. However, they are not perfectly selective. In principle, Plk1 can also be inhibited by interfering with its protein interaction domain, the Polo-Box Domain (PBD)...
May 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28521569/exploring-the-biochemistry-of-the-prenylome-and-its-role-in-disease-through-proteomics-progress-and-potential
#7
Maura Brioschi, Alma Martinez Fernandez, Cristina Banfi
Protein prenylation is a ubiquitous covalent post-translational modification characterized by the addition of farnesyl or geranylgeranyl isoprenoid groups to a cysteine residue located near the carboxyl terminal of a protein. It is essential for the proper localization and cellular activity of numerous proteins, including Ras family GTPases and G-proteins. In addition to its roles in cellular physiology, the prenylation process has important implications in human diseases and in the recent years, it has become attractive target of inhibitors with therapeutic potential...
May 26, 2017: Expert Review of Proteomics
https://www.readbyqxmd.com/read/28520445/telodendrimers-for-physical-encapsulation-and-covalent-linking-of-individual-or-combined-therapeutics
#8
Ashok Kakkar, Jason Choi, Alexandre Moquin, Enzo Bomal, Li Na, Dusica Maysinger
New therapeutics for glioblastoma multiforme and our ability to deliver them using efficient nanocarriers, constitute topical areas of research. We report a comparative study of temozolomide and quercetin in the treatment of glioblastoma (GBM) in 3D, and their incorporation into micelles obtained from synthetically articulated architectural copolymers, and a commercially available linear polymer poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA). A versatile synthetic methodology to telodendrimers which can be easily adapted to the needs of other therapeutic interventions, is presented...
May 18, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28514140/properties-of-intermediates-in-the-catalytic-cycle-of-oxalate-oxidoreductase-and-its-suicide-inactivation-by-pyruvate
#9
Elizabeth Pierce, Steven O Mansoorabadi, Mehmet Can, George H Reed, Stephen W Ragsdale
Oxalate:ferredoxin oxidoreductase (OOR) is an unusual member of the thiamine pyrophosphate (TPP)-dependent 2-oxoacid:ferredoxin oxidoreductase (OFOR) family in that it catalyzes the coenzyme A (CoA)-independent conversion of oxalate into 2 equivalents of carbon dioxide. This reaction is surprising because binding of CoA to the acyl-TPP intermediate of other OFORs results in formation of a CoA ester, and in the case of pyruvate:ferredoxin oxidoreductase (PFOR), CoA binding generates the central metabolic intermediate acetyl-CoA and promotes a 10(5)-fold acceleration of the rate of electron transfer...
May 23, 2017: Biochemistry
https://www.readbyqxmd.com/read/28514117/tailored-ahp-cyclodepsipeptides-as-potent-non-covalent-serine-protease-inhibitors
#10
Steffen Köcher, Juliana Rey, Jens Bongard, Andre N Tiaden, Michael Meltzer, Peter Richards, Michael Ehrmann, Markus Kaiser
The S1 serine protease family is one of the largest and biologically relevant protease families. Despite their biomedical significance, generic approaches to generate potent, class-specific, bioactive non-covalent inhibitors for these enzymes are still limited. Here, we demonstrate that Ahp-cyclodepsipeptides represent a suitable scaffold for generating target-tailored serine protease inhibitors. For efficient synthetic access, we developed a practical mixed solid and solution phase synthesis that we validated by the first chemical synthesis of two natural products, Tasipeptin A and B...
May 17, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28512203/the-mechanism-of-activation-of-irak1-and-irak4-by-interleukin-1-and-toll-like-receptor-agonists
#11
Stefan Vollmer, Sam Strickson, Tinghu Zhang, Nathanael Gray, Katherine Lee, Vikram Rao, Philip Cohen
We have developed the first assays that measure the protein kinase activities of Interleukin-1 Receptor Associated Kinase 1 (IRAK1) and IRAK4 reliably in human cell extracts, by employing Pellino1 as a substrate in conjunction with specific pharmacological inhibitors of IRAK1 and IRAK4. We exploited these assays to show that IRAK4 was constitutively active and that its intrinsic activity towards Pellino1 was not increased significantly by stimulation with interleukin-1 (IL-1) in IL-1R-expressing HEK293 cells, Pam3Csk4-stimulated human THP1 monocytes or primary human macrophages...
May 16, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28512127/a-structure-derived-snap-trap-mechanism-of-a-multispecific-serpin-from-the-dysbiotic-human-oral-microbiome
#12
Theodoros Goulas, Miroslaw Ksiazek, Irene Garcia-Ferrer, Alicja M Sochaj-Gregorczyk, Irena Waligorska, Marcin Wasylewski, Jan Potempa, F Xavier Gomis-Rüth
Enduring host-microbiome relationships are based on adaptive strategies within a particular ecological niche. Tannerella forsythia is a dysbiotic member of the human oral microbiome that inhabits periodontal pockets and contributes to chronic periodontitis. To counteract endopeptidases from the host or microbial competitors, T. forsythia possesses a serpin-type proteinase inhibitor called miropin. While serpins from animals, plants, and viruses have been widely studied, those from prokaryotes have received only limited attention...
May 16, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28507715/a-quantitative-mechanistic-pk-pd-model-directly-connects-btk-target-engagement-and-in-vivo-efficacy
#13
Fereidoon Daryaee, Zhuo Zhang, Kayla R Gogarty, Yong Li, Jonathan Merino, Stewart L Fisher, Peter J Tonge
Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug discovery. Previously we described a mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model that used drug-target binding kinetics to successfully predict the in vivo efficacy of antibacterial compounds in models of Pseudomonas aeruginosa and Staphylococcus aureus infection. In the present work we extend this model to quantitatively correlate the engagement of Bruton's tyrosine kinase (Btk) by the covalent inhibitor CC-292 with the ability of this compound to reduce ankle swelling in an animal model of arthritis...
May 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28498651/design-of-benzoxathiazin-3-one-1-1-dioxides-as-a-new-class-of-irreversible-serine-hydrolase-inhibitors-discovery-of-a-uniquely-selective-pnpla4-inhibitor
#14
Anne F Kornahrens, Armand B Cognetta, Daniel M Brody, Megan L Matthews, Benjamin F Cravatt, Dale L Boger
The design and examination of 4,1,2-benzoxathiazin-3-one 1,1-dioxides as candidate serine hydrolase inhibitors are disclosed, and represent the synthesis and study of a previously unexplored heterocycle. This new class of activated cyclic carbamates provided selective irreversible inhibition of a small subset of serine hydrolases without release of a leaving group, does not covalently modify active site catalytic cysteine and lysine residues of other enzyme classes, and was found to be amenable to predictable structural modifications that modulate intrinsic reactivity or active site recognition...
May 12, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28484248/hydration-effects-on-the-efficacy-of-the-epidermal-growth-factor-receptor-kinase-inhibitor-afatinib
#15
Srinivasaraghavan Kannan, Mohan R Pradhan, Garima Tiwari, Wei-Chong Tan, Balram Chowbay, Eng Huat Tan, Daniel Shao-Weng Tan, Chandra Verma
Small molecules targeting the EGFR tyrosine kinase domain have been used with some success at treating patients with non-small cell lung cancer driven by activating mutations in the kinase domain. The initial class of inhibitors displaced ATP noncovalently but were rendered ineffective due to the development of resistance mutations in the kinase domain. These were overcome by the development of covalent inhibitors such as afatinib which also bind in the ATP pocket. However pooled analysis of two recent clinical trials LUX-3 and LUX-6 demonstrated an unprecedented overall survival benefit of afatinib over chemotherapy for the EGFR (19del) , but not the EGFR (L858R) ...
May 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28476891/drosophila-tg-a-transglutaminase-is-secreted-via-an-unconventional-golgi-independent-mechanism-involving-exosomes-and-two-types-of-fatty-acylations
#16
Toshio Shibata, Jinki Hadano, Daichi Kawasaki, Xiaoqing Dong, Shun-Ichiro Kawabata
Transglutaminases (TGs) play essential intracellular and extracellular roles by covalently cross-linking many proteins. Drosophila TG is encoded by one gene and has two alternative splicing-derived isoforms, TG-A and TG-B, which contain distinct N-terminal 46- and 38-amino acid sequences, respectively. The TGs identified to date do not have a typical endoplasmic reticulum (ER)-signal peptide, and the molecular mechanisms of their secretion under physiologic conditions are unclear. Immunocytochemistry revealed that TG-A localizes to multivesicular-like structures, whereas TG-B localizes to the cytosol...
May 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28476645/withaferin-a-a-natural-compound-with-anti-tumor-activity-is-a-potent-inhibitor-of-transcription-factor-c-ebp%C3%AE
#17
Kim D Falkenberg, Anke Jakobs, Julian C Matern, Wolfgang Dörner, Sagar Uttarkar, Amke Trentmann, Simone Steinmann, Anna Coulibaly, Caroline Schomburg, Henning D Mootz, Thomas J Schmidt, Karl-Heinz Klempnauer
Recent work has shown that deregulation of the transcription factor Myb contributes to the development of leukemia and several other human cancers, making Myb and its cooperation partners attractive targets for drug development. By employing a myeloid Myb-reporter cell line we have identified Withaferin A (WFA), a natural compound that exhibits anti-tumor activities, as an inhibitor of Myb-dependent transcription. Analysis of the inhibitory mechanism of WFA showed that WFA is a significantly more potent inhibitor of C/EBPβ, a transcription factor cooperating with Myb in myeloid cells, than of Myb itself...
May 2, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28474886/multivalent-soluble-antigen-arrays-exhibit-high-avidity-binding-and-modulation-of-b-cell-receptor-mediated-signaling-to-drive-efficacy-against-experimental-autoimmune-encephalomyelitis
#18
Brittany L Hartwell, Chad J Pickens, Martin Leon, Cory Berkland
A pressing need exists for antigen-specific immunotherapies (ASIT) that induce selective tolerance in autoimmune disease while avoiding deleterious global immunosuppression. Multivalent soluble antigen arrays (SAgAPLP:LABL), consisting of a hyaluronic acid (HA) linear polymer backbone cografted with multiple copies of autoantigen (PLP) and cell adhesion inhibitor (LABL) peptides, are designed to induce tolerance to a specific multiple sclerosis (MS) autoantigen. Previous studies established that hydrolyzable SAgAPLP:LABL, employing a degradable linker to codeliver PLP and LABL, was therapeutic in experimental autoimmune encephalomyelitis (EAE) in vivo and exhibited antigen-specific binding with B cells, targeted the B cell receptor (BCR), and dampened BCR-mediated signaling in vitro...
May 17, 2017: Biomacromolecules
https://www.readbyqxmd.com/read/28470171/co-delivery-of-paclitaxel-and-tetrandrine-via-irgd-peptide-conjugated-lipid-polymer-hybrid-nanoparticles-overcome-multidrug-resistance-in-cancer-cells
#19
Jinming Zhang, Lu Wang, Hon Fai Chan, Wei Xie, Sheng Chen, Chengwei He, Yitao Wang, Meiwan Chen
One of the promising strategies to overcome tumor multidrug resistance (MDR) is to deliver anticancer drug along with P-glycoprotein (P-gp) inhibitor simultaneously. To enhance the cancer cellular internalization and implement the controlled drug release, herein an iRGD peptide-modified lipid-polymer hybrid nanosystem (LPN) was fabricated to coload paclitaxel (PTX) and tetrandrine (TET) at a precise combination ratio. In this co-delivery system, PTX was covalently conjugated to poly (D,L-lactide-co-glycolide) polymeric core by redox-sensitive disulfide bond, while TET was physically capsulated spontaneously for the aim to suppress P-gp in advance by the earlier released TET in cancer cells...
May 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28467801/inhibition-of-exportin-1-function-results-in-rapid-cell-cycle-associated-dna-damage-in-cancer-cells
#20
Russell T Burke, Joshua M Marcus, James D Orth
Selective inhibitors of nuclear export (SINE) are small molecules in development as anti-cancer agents. The first-in-class SINE, selinexor, is in clinical trials for blood and solid cancers. Selinexor forms a covalent bond with exportin-1 at cysteine-528, and blocks its ability to export cargos. Previous work has shown strong cell cycle effects and drug-induced cell death across many different cancer-derived cell lines. Here, we report strong cell cycle-associated DNA double-stranded break formation upon the treatment of cancer cells with SINE...
April 12, 2017: Oncotarget
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