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ACS Chemical Biology

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https://www.readbyqxmd.com/read/28644609/galnac-tyrosine-is-a-ligand-of-plant-lectins-antibodies-and-human-and-murine-macrophage-galactose-type-lectins
#1
Ruslan Gibadullin, David Wayne Farnsworth, Joseph J Barchi, Jeffrey C Gildersleeve
In 2011, a new type of protein O-glycosylation was discovered in which N-acetylgalactosamine is attached to the side chain of tyrosine (GalNAc-Tyr). While present on dozens of proteins, the biological roles of GalNAc-Tyr are unknown. To gain insight into this new type of modification, we synthesized a group of GalNAc-Tyr glycopeptides, constructed microarrays, and evaluated potential recognition of GalNAc-Tyr by a series of glycan-binding proteins. Through a series of >150 microarray experiments, we assessed binding properties of a variety of plant lectins, monoclonal antibodies, and endogenous lectins...
June 23, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28636317/downsizing-proto-oncogene-cfos-to-short-helix-constrained-peptides-that-bind-jun
#2
Daniel Baxter, Samuel R Perry, Timothy A Hill, W Mei Kok, Nathan R Zaccai, R Leo Brady, David P Fairlie, Jody M Mason
The oncogenic transcription factor activator protein-1 (AP-1) is a DNA-binding protein that assembles through dimerization of Fos and Jun protein subunits, their leucine-rich helical sequences entwining into a coiled-coil structure. This study reports on downsizing the proto-oncogene cFos protein (380 residues) to shorter peptides (37-25 residues) modified with helix-inducing constraints to enhance binding to Jun. A crystal structure is reported for a 37-residue Fos-derived peptide (FosW) bound to Jun. This guided iterative downsizing of FosW to shorter peptide sequences that were constrained into stable water-soluble α-helices by connecting amino acid side chains to form cyclic pentapeptide components...
June 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28636309/quantitative-chemical-proteomic-profiling-of-the-in-vivo-targets-of-reactive-drug-metabolites
#3
Landon R Whitby, R Scott Obach, Gabriel M Simon, Matthew M Hayward, Benjamin F Cravatt
Idiosyncratic liver toxicity represents an important problem in drug research and pharmacotherapy. Reactive drug metabolites that modify proteins are thought to be a principal factor in drug-induced liver injury. Here, we describe a quantitative chemical proteomic method to identify the targets of reactive drug metabolites in vivo. Treating mice with clickable analogues of four representative hepatotoxic drugs, we demonstrate extensive covalent binding that is confined primarily to the liver. Each drug exhibited a distinct target profile that, in certain cases, showed strong enrichment for specific metabolic pathways (e...
June 21, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28628310/furoxan-nitric-oxide-donors-disperse-pseudomonas-aeruginosa-biofilms-accelerate-growth-and-repress-pyoverdine-production
#4
Wee Han Poh, Nicolas Barraud, Stefano Guglielmo, Loretta Lazzarato, Barbara Rolando, Roberta Fruttero, Scott A Rice
The use of nitric oxide (NO) as a signal for biofilm dispersal has been shown to increase the susceptibility of many biofilms to antibiotics, promoting their eradication. The delivery of NO to biofilms can be achieved by using NO-donors with different kinetics and properties of NO release that can influence their efficacy as biofilm control agents. In this study, the kinetics of three furoxan-derivatives were evaluated. The effects of these NO-donors, which have an advantageous pharmacological profile of slower onset with an extended duration of action, on Pseudomonas aeruginosa growth, biofilm development and dispersal were also characterized...
June 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28628306/lysine-deacetylation-by-hdac6-regulates-the-kinase-activity-of-akt-in-human-neural-progenitor-cells
#5
Jonathan Iaconelli, Jasmin Lalonde, Bradley Watmuff, Bangyan Liu, Ralph Mazitschek, Stephen J Haggarty, Rakesh Karmacharya
AKT family of serine-threonine kinases functions downstream of phosphatidylinositol 3-kinase (PI3K) to transmit signals by direct phosphorylation of a number of targets, including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and β-catenin. AKT binds to phosphatidylinositol (3,4,5)-triphosphate (PIP3) generated by PI3K activation, which results in its membrane localization and subsequent activation through phosphorylation by phosphoinositide-dependent protein kinase 1 (PDK1)...
June 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28541657/chemical-modulation-of-protein-o-glcnacylation-via-ogt-inhibition-promotes-human-neural-cell-differentiation
#6
Lissette M Andres, Ian W Blong, Angela C Evans, Neil G Rumachik, Teppei Yamaguchi, Nam D Pham, Pamela Thompson, Jennifer J Kohler, Carolyn R Bertozzi
The enzymes that determine protein O-GlcNAcylation, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), act on key transcriptional and epigenetic regulators, and both are abundantly expressed in the brain. However, little is known about how alterations in O-GlcNAc cycling affect human embryonic stem cell (hESC) neural differentiation. Here, we studied the effects of perturbing O-GlcNAcylation during neural induction of hESCs using the metabolic inhibitor of OGT, peracetylated 5-thio-N-acetylglucosamine (Ac4-5SGlcNAc)...
June 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28621933/structural-flexibility-of-an-inhibitor-overcomes-drug-resistance-mutations-in-staphylococcus-aureus-ftsz
#7
Junso Fujita, Yoko Maeda, Eiichi Mizohata, Tsuyoshi Inoue, Malvika Kaul, Ajit K Parhi, Edmond J LaVoie, Daniel S Pilch, Hiroyoshi Matsumura
In the effort to combat antibiotic resistance, inhibitors of the essential bacterial protein FtsZ have emerged as a promising new class of compounds with clinical potential. One such FtsZ inhibitor (TXA707) is associated with potent activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) that are resistant to current standard-of-care antibiotics. However, mutations in S. aureus FtsZ (SaFtsZ) that confer resistance to TXA707 have been observed, with mutations in the Gly196 and Gly193 residues being among the most prevalent...
June 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28586195/ex-vivo-cell-based-screening-platform-for-modulators-of-hepatosteatosis
#8
Shan Yu, Emily Chen, Lance Sherwood, Mitchell Hull, Ashley K Woods, Matthew S Tremblay
Nonalcoholic fatty liver disease (NAFLD) is the result of the ectopic accumulation of lipids in hepatic cells and is the early stage of liver diseases including fibrosis, cirrhosis, and hepatocellular carcinoma. While some mechanisms of aberrant lipid storage are understood, unbiased phenotypic drug screening holds the potential to identify new therapeutic small molecule mechanisms that reverse lipid accumulation in hepatic cells and prevent disease progression. Immortalized hepatocyte cell lines are often used as in vitro models of hepatocyte function, including in the study of lipid accumulation...
June 16, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28617580/progressive-stereo-locking-psl-a-residual-dipolar-coupling-based-force-field-method-for-determining-the-relative-configuration-of-natural-products-and-other-small-molecules
#9
Gabriel Cornilescu, René F Ramos Alvarenga, Thomas P Wyche, Tim S Bugni, Roberto R Gil, Claudia C Cornilescu, William M Westler, John L Markley, Charles D Schwieters
Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to allow free sampling of both R and S configurations of the stereocenters of interest. The algorithm uses a floating alignment tensor in a simulated annealing protocol to identify the conformations and configurations that best fit experimental RDC and distance restraints (from NOE and J-coupling data)...
June 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28617578/antibodies-against-specific-muc16-glycosylation-sites-inhibit-ovarian-cancer-growth
#10
Thapi Dharma Rao, Alberto Fernández-Tejada, Abram Axelrod, Nestor Rosales, Xiujun Yan, Sahityasri Thapi, Amy Wang, Kay J Park, Brandon Nemieboka, Jingyi Xiang, Jason S Lewis, Nariso Olvera, Douglas A Levine, Samuel J Danishefsky, David Spriggs
Expression of the retained C-terminal extracellular portion of the ovarian cancer glycoprotein MUC16 induces transformation and tumor growth. However, the mechanisms of MUC16 oncogenesis related to glycosylation are not clearly defined. We establish that MUC16 oncogenic effects are mediated through MGAT5-dependent N-glycosylation of two specific asparagine sites within its 58 amino acid ectodomain. Oncogenic signaling from the C-terminal portion of MUC16 requires the presence of Galectin-3 and growth factor receptors co-localized on lipid rafts...
June 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28617577/imaging-with-mass-spectrometry-of-bacteria-on-the-exoskeletons-of-fungus-growing-ants
#11
Erin Gemperline, Heidi A Horn, Kellen DeLaney, Cameron R Currie, Lingjun Li
Mass spectrometry imaging is a powerful analytical technique for detecting and determining spatial distributions of molecules within a sample. Typically mass spectrometry imaging is limited to the analysis of thin tissue sections taken from the middle of a sample. In this work, we present a mass spectrometry imaging method for the detection of compounds produced by bacteria on the outside surface of ant exoskeletons in response to pathogen exposure. Fungus-growing ants have a specialized mutualism with Pseudonocardia, a bacterium that lives on the ants' exoskeleton and helps protect their fungal garden food source from harmful pathogens...
June 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28613823/inhibition-of-mitochondrial-bioenergetics-by-esterase-triggered-cos-h2s-donors
#12
Andrea K Steiger, Michela Marcatti, Csaba Szabo, Bartosz Szczesny, Michael D Pluth
Hydrogen sulfide (H2S) is an important biological mediator, and synthetic H2S donating molecules provide an important class of investigative tools for H2S research. Here we report esterase-activated H2S donors that function by first releasing carbonyl sulfide (COS), which is rapidly converted to H2S by the ubiquitous enzyme carbonic anhydrase (CA). We report the synthesis, self-immolative decomposition, and H2S release profiles of the developed scaffolds. In addition, the developed esterase-triggered COS/H2S donors exhibit higher levels of cytotoxicity than equivalent levels of Na2S or the common H2S donors GYY4137 and AP39...
June 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28613820/protein-modification-by-endogenously-generated-lipid-electrophiles-mitochondria-as-the-source-and-target
#13
William N Beavers, Kristie L Rose, James J Galligan, Michelle M Mitchener, Carol A Rouzer, Keri A Tallman, Connor R Lamberson, Xiaojing Wang, Salisha Hill, Pavlina T Ivanova, H Alex Brown, Bing Zhang, Ned A Porter, Lawrence J Marnett
Determining the impact of lipid electrophile-mediated protein damage that occurs during oxidative stress requires a comprehensive analysis of electrophile targets adducted under pathophysiological conditions. Incorporation of ω-alkynyl linoleic acid into the phospholipids of macrophages prior to activation by Kdo2-lipid A, followed by protein extraction, click chemistry and streptavidin affinity capture, enabled a systems-level survey of proteins adducted by lipid electrophiles generated endogenously during the inflammatory response...
June 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28613814/2-chloropropionamide-as-a-low-reactivity-electrophile-for-irreversible-small-molecule-probe-identification
#14
Dharmaraja Allimuthu, Drew J Adams
Resurgent interest in covalent target engagement in drug discovery has demonstrated that small molecules containing weakly reactive electrophiles can be safe and effective therapies. Several recently FDA-approved drugs feature an acrylamide functionality to selectively engage cysteine side chains of kinases (Ibrutinib, Afatinib, and Neratinib). Additional electrophilic functionalities whose reactivity is compatible with highly selective target engagement and in vivo application could open new avenues in covalent small molecule discovery...
June 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28612602/oxygen-dependent-globin-coupled-sensor-signaling-modulates-motility-and-virulence-of-the-plant-pathogen-pectobacterium-carotovorum
#15
Justin L Burns, Parth B Jariwala, Shannon Rivera, Benjamin M Fontaine, Laura Briggs, Emily E Weinert
Bacterial pathogens utilize numerous signals to identify the presence of their host and coordinate changes in gene expression that allow for infection. Within plant pathogens, these signals typically include small molecules and/or proteins from their plant hosts and bacterial quorum sensing molecules to ensure sufficient bacterial cell density for successful infection. In addition, bacteria use environmental signals to identify conditions when the host defenses are weakened and potentially to signal entry into an appropriate host/niche for infection...
June 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28609614/direct-monitoring-of-protein-o-glcnacylation-by-high-resolution-native-mass-spectrometry
#16
Aneika C Leney, Karim Rafie, Daan M F Van Aalten, Albert J R Heck
O-GlcNAcylation is one of the most abundant metazoan nuclear-cytoplasmic post-translational modifications. Proteins modified by O-GlcNAc play key cellular roles in signaling, transcription, metabolism and cell division. Mechanistic studies on protein O-GlcNAcylation are hampered by the lack of methods that can simultaneously quantify O-GlcNAcylation, determine its stoichiometry and monitor O-GlcNAcylation kinetics. Here we demonstrate that high-resolution native mass spectrometry can be employed to monitor the small mass shifts induced by modification by O-GlcNAc on two known protein substrates; CK2α and TAB1, without the need for radioactive labelling or chemoenzymatic tagging using large mass tags...
June 13, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28605180/a-hydrogel-microsphere-drug-delivery-system-that-supports-once-monthly-administration-of-a-glp-1-receptor-agonist
#17
Eric L Schneider, Brian R Hearn, Samuel J Pfaff, Ralph Reid, David G Parkes, Niels Vrang, Gary W Ashley, Daniel V Santi
We have developed a chemically-controlled very long-acting delivery system to support once-monthly administration of a peptidic GLP-1R agonist. Initially, the prototypical GLP-1R agonist exenatide was covalently attached to hydrogel microspheres by a self-cleaving β-eliminative linker; after subcutaneous injection in rats the peptide was slowly released into the systemic circulation. However, the short serum exenatide half-life suggested its degradation in the subcutaneous depot. We found that exenatide undergoes deamidation at Asn(28)with an in vitro and in vivo half-life of approximately two weeks...
June 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28585805/ligand-specific-restriction-of-extracellular-conformational-dynamics-constrains-signaling-of-the-m2-muscarinic-receptor
#18
Marcel Bermudez, Andreas Bock, Fabian Krebs, Ulrike Holzgrabe, Klaus Mohr, Martin J Lohse, Gerhard Wolber
G protein-coupled receptors transmit extracellular signals across cell membranes via different G protein classes and β-arrestins. Some pathways may be therapeutically beneficial, whereas others may be detrimental under certain pathophysiological conditions. For many GPCRs, biased agonists are available, which preferentially signal through one pathway or a subset of pathways, and harnessing biased agonism could be a potential novel therapeutic strategy. However, the incomplete mechanistic understanding of biased agonism hampers rational design of biased ligands...
June 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28541665/identification-of-small-molecule-translesion-synthesis-inhibitors-that-target-the-rev1-ct-rir-protein-protein-interaction
#19
Vibhavari Sail, Alessandro A Rizzo, Nimrat Chatterjee, Radha C Dash, Zuleyha Ozen, Graham C Walker, Dmitry M Korzhnev, M Kyle Hadden
Translesion synthesis (TLS) is an important mechanism through which proliferating cells tolerate DNA damage during replication. The mutagenic Rev1/Polζ-dependent branch of TLS helps cancer cells survive first-line genotoxic chemotherapy and introduces mutations that can contribute to the acquired resistance so often observed with standard anticancer regimens. As such, inhibition of Rev1/Polζ-dependent TLS has recently emerged as a strategy to enhance the efficacy of first-line chemotherapy and reduce the acquisition of chemoresistance by decreasing tumor mutation rate...
June 9, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28570054/directing-the-heterologous-production-of-specific-cyanobacterial-toxin-variants
#20
Tianzhe Liu, Rabia Mazmouz, Sarah E Ongley, Rocky Chau, Russell Pickford, Jason N Woodhouse, Brett A Neilan
Microcystins are globally the most commonly occurring freshwater cyanotoxins, causing acute poisoning and chronically inducing hepatocellular carcinoma. However, the detection and toxicological study of microcystins is hampered by the limited availability and high cost of pure toxin standards. Biosynthesis of microcystin variants in a fast-growing heterologous host offers a promising method of achieving reliable and economically viable alternative to isolating toxin from slow-growing cyanobacterial cultures...
June 7, 2017: ACS Chemical Biology
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