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https://www.readbyqxmd.com/read/29785610/evaluation-of-strategies-for-the-assessment-of-drug-drug-interactions-involving-cytochrome-p450-enzymes
#1
Jelle Reinen, Martijn Smit, Mira Wenker
BACKGROUND AND OBJECTIVES: Drug-drug interactions (DDIs) can occur when one drug alters the metabolism of another drug. Drug metabolism mediated by cytochrome P450 enzymes (CYPs) is responsible for the majority of metabolism of known drugs and inhibition of CYP enzymes is a well-known cause of DDIs. In the current study, the use of various human liver microsomes (HLM)-based methods to determine occurrence of CYP-mediated metabolism-dependent inhibition (MDI) and possible follow-up studies were evaluated...
May 21, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29784649/small-molecular-inhibitors-targeting-protein-sumoylation-as-novel-anticancer-compounds
#2
Yanfang Yang, Zijing Xia, Xixi Wang, Xinyu Zhao, Zenghua Sheng, Yang Ye, Gu He, Liangxue Zhou, Hongxia Zhu, Ningzhi Xu, Shufang Liang
SUMOylation, one of post-translational modifications, is covalently modified on lysine residues of a target protein through an enzymatic cascade reaction similar to protein ubiquitination. Along with identification of many SUMOylated proteins, protein SUMOylation has been proven to regulate multiple biological activities including transcription, cell cycle, DNA repair and innate immunity. The dysregulation of protein SUMOylation and deSUMOylation modification is linked with carcinogenesis and tumor progression...
May 21, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29783099/leveraging-the-cruzain-s3-subsite-to-increase-affinity-for-reversible-covalent-inhibitors
#3
Lorenzo Cianni, Geraldo Sartori, Fabiana Rosini, Daniela De Vita, Gabriel Pires, Bianca Rebelo Lopes, Andrei Leitão, Antonio C B Burtoloso, Carlos A Montanari
Cruzain is the major cysteine protease of Trypanosoma cruzi, the etiological agent of Chagas disease. Reversible covalent cruzain inhibitors can block the steps of cell differentiation in the parasite and kill the organism. To this end, the description of how inhibitors modified at the P2/P3 positions lead to analogs with greater cruzain affinity to the S2/S3 subsites is of fundamental importance. Albeit many efforts are being employed in the characterization of the interaction processes with S2 subsite, little is known about the cruzain S3 subsite...
April 26, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29782144/the-nitro-group-as-a-masked-electrophile-in-covalent-enzyme-inhibition
#4
Sneha Ray, Dale F Kreitler, Andrew M Gulick, Andrew S Murkin
We report the unprecedented reaction between a nitroalkane and an active-site cysteine residue to yield a thiohydroximate adduct. Structural and kinetic evidence suggests the nitro group is activated by conversion to its nitronic acid tautomer within the active site. The nitro group, therefore, shows promise as a masked electrophile in the design of covalent inhibitors targeting binding pockets with appropriately placed cysteine and general acid residues.
May 21, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/29781013/design-and-synthesis-of-aza-indolyl-maleimide-based-covalent-inhibitors-of-glycogen-synthase-kinase-3%C3%AE
#5
Zhimin Yang, Hui Liu, Botao Pan, Fengli He, Zhengying Pan
As an important kinase in multiple signal transduction pathways, GSK-3β has been an attractive target for chemical probe discovery and drug development. Compared to numerous reversible inhibitors that have been developed, covalent inhibitors of GSK-3β are noticeably lacking. Here, we report the discovery of a series of covalent GSK-3β inhibitors by optimizing both non-covalent interactions and reactive groups. Among these covalent inhibitors, compound 38b with a mild α-fluoromethyl amide reactive group emerges as a selective and covalent inhibitor against GSK-3β, effectively inhibits the phosphorylation of glycogen synthase and tau protein, and increases β-catenin's levels in living cells...
May 21, 2018: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/29779956/targeted-covalent-inhibition-of-prolyl-oligopeptidase-pop-discovery-of-sulfonylfluoride-peptidomimetics
#6
Salvador Guardiola, Roger Prades, Laura Mendieta, Arwin J Brouwer, Jelle Streefkerk, Laura Nevola, Teresa Tarragó, Rob M J Liskamp, Ernest Giralt
Prolyl oligopeptidase (POP), a serine protease highly expressed in the brain, has recently emerged as an enticing therapeutic target for the treatment of cognitive and neurodegenerative disorders. However, most reported inhibitors suffer from short duration of action, poor protease selectivity, and low blood-brain barrier (BBB) permeability, which altogether limit their potential as drugs. Here, we describe the structure-based design of the first irreversible, selective, and brain-permeable POP inhibitors. At low-nanomolar concentrations, these covalent peptidomimetics produce a fast, specific, and sustained inactivation of POP, both in vitro and in human cells...
May 7, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29778873/bioanalysis-of-ibrutinib-and-its-dihydrodiol-and-glutathione-cycle-metabolites-by-liquid-chromatography-tandem-mass-spectrometry
#7
J J M Rood, P J A Dormans, M J van Haren, J H M Schellens, J H Beijnen, R W Sparidans
Ibrutinib is a targeted covalent inhibitor frequently used for the treatment of various lymphomas. In addition to oxidative metabolism, it is metabolized through glutathione coupling. The quantitative insight into this kind of metabolism is scarce, and tools for quantitation are lacking. The non-oxidative metabolism could prove a more prominent role when oxidative metabolism is impaired. Also, in-vitro studies could over-estimate the effect of CYP450-inhibition. To gain quantitative insight into this relatively unknown biotransformation pathway of the drug we have developed a validated simple, fast and sensitive bio-analytical assay for ibrutinib, dihydrodiol-ibrutinib, and the glutathione, cysteinylglycine and cysteine conjugates of ibrutinib in human plasma...
May 11, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29767965/bifunctional-chimera-that-coordinately-targets-human-immunodeficiency-virus-1-hiv-1-envelope-gp120-and-host-cell-ccr5-co-receptor-at-the-virus-cell-interface
#8
Adel A Rashad, Li-Rui Song, Andrew P Holmes, Kriti Acharya, Shiyu Zhang, Zhi-Long Wang, Ebony Gary, Xin Xie, Vanessa Pirrone, Michele A Kutzler, Ya-Qiu Long, Irwin Chaiken
To address the urgent need for new agents to reduce the global occurrence and spread of AIDS, we investigated the underlying hypothesis that antagonists of HIV-1 Envelope (Env) gp120 and host cell co-receptor (CoR) proteins can be covalently joined into bifunctional synergistic combinations that will improve antiviral. A synthetic protocol was established to covalently combine a CCR5 small molecule antagonist and a gp120 peptide triazole antagonist to form the bifunctional chimera. Importantly, the chimeric inhibitor preserved the specific targeting properties of the two separate chimera components, and at the same time exhibited low to sub-nanomolar potencies, in inhibiting cell infection by different pseudoviruses, that were substantially greater than those of a non-covalent mixture of individual components...
May 16, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29765556/antibody-assisted-target-identification-reveals-afatinib-an-egfr-covalent-inhibitor-down-regulating-ribonucleotide-reductase
#9
Cheng-Han Yu, Chi-Chi Chou, Hsin-Fang Tu, Wei-Chieh Huang, Ya-Yeh Ho, Kay-Hooi Khoo, Ming-Shyue Lee, Geen-Dong Chang
Afatinib, used for the first-line treatment of non-small-cell lung carcinoma (NSCLC) patients with distinct epidermal growth factor receptor (EGFR) mutations, inactivates EGFR by mimicking ATP structure and forming a covalent adduct with EGFR. We developed a method to unravel potential targets of afatinib in NSCLC cells through immunoprecipitation of afatinib-labeling proteins with anti-afatinib antiserum and mass spectrometry analysis. Ribonucleotide reductase (RNR) is one of target proteins of afatinib revealed by this method...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29760531/the-reactivity-driven-biochemical-mechanism-of-covalent-kras-g12c-inhibitors
#10
Rasmus Hansen, Ulf Peters, Anjali Babbar, Yuching Chen, Jun Feng, Matthew R Janes, Lian-Sheng Li, Pingda Ren, Yi Liu, Patrick P Zarrinkar
Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRASG12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRASG12C , while the reversible binding affinity is weak, in the hundreds of micromolar or higher range...
May 14, 2018: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/29760386/rapid-labelling-and-covalent-inhibition-of-intracellular-native-proteins-using-ligand-directed-n-acyl-n-alkyl-sulfonamide
#11
Tomonori Tamura, Tsuyoshi Ueda, Taiki Goto, Taku Tsukidate, Yonatan Shapira, Yuki Nishikawa, Alma Fujisawa, Itaru Hamachi
Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand-directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as a reactive group. Quantitative kinetic analyses reveal that ligand-directed N-acyl-N-alkyl sulfonamide chemistry allows for rapid modification of a lysine residue proximal to the ligand binding site of a target protein, with a rate constant of ~104  M-1  s-1 , comparable to the fastest bioorthogonal chemistry...
May 14, 2018: Nature Communications
https://www.readbyqxmd.com/read/29757973/a-new-strategy-to-control-and-eradicate-undruggable-oncogenic-k-ras-driven-pancreatic-cancer-molecular-insights-and-core-principles-learned-from-developmental-and-evolutionary-biology
#12
REVIEW
Robert E Van Sciver, Michael P Lee, Caroline Dasom Lee, Alex C Lafever, Elizaveta Svyatova, Kevin Kanda, Amber L Colliver, Lauren L Siewertsz van Reesema, Angela M Tang-Tan, Vasilena Zheleva, Monicah N Bwayi, Minglei Bian, Rebecca L Schmidt, Lynn M Matrisian, Gloria M Petersen, Amy H Tang
Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely "undruggable". Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH)...
May 14, 2018: Cancers
https://www.readbyqxmd.com/read/29754826/atomic-resolution-cryo-em-structure-of-%C3%AE-galactosidase
#13
Alberto Bartesaghi, Cecilia Aguerrebere, Veronica Falconieri, Soojay Banerjee, Lesley A Earl, Xing Zhu, Nikolaus Grigorieff, Jacqueline L S Milne, Guillermo Sapiro, Xiongwu Wu, Sriram Subramaniam
The advent of direct electron detectors has enabled the routine use of single-particle cryo-electron microscopy (EM) approaches to determine structures of a variety of protein complexes at near-atomic resolution. Here, we report the development of methods to account for local variations in defocus and beam-induced drift, and the implementation of a data-driven dose compensation scheme that significantly improves the extraction of high-resolution information recorded during exposure of the specimen to the electron beam...
April 30, 2018: Structure
https://www.readbyqxmd.com/read/29753682/class-a-%C3%AE-lactamases-and-inhibitors-in-silico-analysis-of-the-binding-mode-and-the-relationship-with-resistance
#14
Rebeca Pereira, Vitor Won-Held Rabelo, Alexander Sibajev, Paula Alvarez Abreu, Helena Carla Castro
β-lactams are one of the most common antimicrobials used to treat bacterial infections. However, bacterial resistance has compromised their efficacy, mainly due to β-lactamase enzyme production. To overcome this resistance, β-lactamase inhibitors can be used in association with these antimicrobials. Herein, we analyzed the structural characteristics of β-lactamases and their interactions with classical inhibitors, such as clavulanic acid (CA), sulbactam (SB) and tazobactam (TZ) to gain insights into resistance...
May 10, 2018: Journal of Biotechnology
https://www.readbyqxmd.com/read/29750408/non-covalent-small-molecule-kelch-like-ech-associated-protein-1-nuclear-factor-erythroid-2-related-factor-2-keap1-nrf2-inhibitors-and-their-potential-for-targeting-cns-diseases
#15
Jakob S Pallesen, Kim Tai Tran, Anders Bach
The transcription factor Nrf2 has a protective effect against oxidative stress and plays a major role in inflammation and CNS diseases. Inhibition of the protein-protein interaction (PPI) between Nrf2 and its repressor protein Keap1 leads to translocation of Nrf2 from the cytosol to the nucleus and expression of detoxifying antioxidant enzymes. To date, several non-covalent small-molecule Keap1-Nrf2 inhibitors have been identified; however, many of them contain carboxylic acids and are rather large in size, which likely prevents or decreases CNS permeability...
May 11, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29748982/redox-responsive-polymer-with-self-immolative-linkers-for-the-release-of-payloads
#16
Supitchaya Iamsaard, Farzad Seidi, Naruphorn Dararatana, Daniel Crespy
Previous couplings of corrosion inhibitors to redox-responsive polymers via covalent bonding suffer from several drawbacks. It is presented here novel redox-responsive polymer-corrosion inhibitor conjugates that contain self-immolative linkers in their side chains. Very fast redox-induced release of tryptamine, a drug and a corrosion inhibitor, is observed after applying a reductive trigger.
May 11, 2018: Macromolecular Rapid Communications
https://www.readbyqxmd.com/read/29746956/liposomal-delivery-of-a-pin1-inhibitor-complexed-with-cyclodextrins-as-new-therapy-for-high-grade-serous-ovarian-cancer
#17
Concetta Russo Spena, Lucia De Stefano, Stefano Palazzolo, Barbara Salis, Carlotta Granchi, Filippo Minutolo, Tiziano Tuccinardi, Roberto Fratamico, Sara Crotti, Sara D'Aronco, Marco Agostini, Giuseppe Corona, Isabella Caligiuri, Vincenzo Canzonieri, Flavio Rizzolio
Pin1, a prolyl isomerase that sustains tumor progression, is overexpressed in different types of malignancies. Functional inactivation of Pin1 restrains tumor growth and leaves normal cells unaffected making it an ideal pharmaceutical target. Although many studies on Pin1 have focused on malignancies that are influenced by sex hormones, studies in ovarian cancer have lagged behind. Here, we show that Pin1 is an important therapeutic target in high-grade serous epithelial ovarian cancer. Knock down of Pin1 in ovarian cancer cell lines induces apoptosis and restrains tumor growth in a syngeneic mouse model...
May 7, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29746087/mechanism-of-action-of-mycobacterium-tuberculosis-gyrase-inhibitors-a-novel-class-of-gyrase-poisons
#18
Elizabeth G Gibson, Tim R Blower, Monica Cacho, Ben David Bax, James M Berger, Neil Osheroff
Tuberculosis is one of the leading causes of morbidity worldwide and the incidences of drug resistance and intolerance are prevalent. Thus, there is a desperate need for the development of new anti-tubercular drugs. Mycobacterium tuberculosis gyrase inhibitors (MGIs) are napthyridone/aminopiperidine-based drugs that display activity against M. tuberculosis cells and tuberculosis in mouse models [Blanco, D., et al. (2015) Antimicrob. Agents Chemother. 59, 1868-1875]. Genetic and mutagenesis studies suggest that gyrase, which is the target for fluoroquinolone antibacterials, is also the target for MGIs...
May 10, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29743665/isozyme-specific-comprehensive-characterization-of-transglutaminase-crosslinked-substrates-in-kidney-fibrosis
#19
Hideki Tatsukawa, Risa Otsu, Yuji Tani, Ryosuke Wakita, Kiyotaka Hitomi
Chronic kidney disease is characterized by prolonged decline in renal function, excessive accumulation of ECM, and progressive tissue fibrosis. Transglutaminase (TG) is a crosslinking enzyme that catalyzes the formation of covalent bonds between glutamine and lysine residues, and is involved in the induction of renal fibrosis via the stabilization of ECM and the activation of TGF-β1. Despite the accumulating evidences indicating that TG2 is a key enzyme in fibrosis, genetic knockout of TG2 reduced by only 50% the elevated protein crosslinking and fibrous protein in renal fibrosis model, whereas treatment with TG inhibitor almost completely reduced these levels...
May 9, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29743376/transmembrane-protein-pul50-of-human-cytomegalovirus-inhibits-isgylation-by-downregulating-ube1l
#20
Myoung Kyu Lee, Ye Ji Kim, Young-Eui Kim, Tae-Hee Han, Jens Milbradt, Manfred Marschall, Jin-Hyun Ahn
Interferon-stimulated gene (ISG) 15 encodes a ubiquitin-like protein that can be conjugated to proteins via an enzymatic cascade involving the E1, E2, and E3 enzymes. ISG15 expression and protein ISGylation modulate viral infection; however, the viral mechanisms regulating the function of ISG15 and ISGylation are not well understood. We recently showed that ISGylation suppresses the growth of human cytomegalovirus (HCMV) at multiple steps of the virus life cycle, and that the virus-encoded pUL26 protein inhibits protein ISGylation...
May 9, 2018: Journal of Virology
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