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ACS chemical biology 37건

  1. [해외논문]   Cell-Density Dependence of Host-Defense Peptide Activity and Selectivity in the Presence of Host Cells   SCIE

    Savini, Filippo (Department of Biochemical Sciences “A. Rossi Fanelli”, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, ) , Luca, Vincenzo (Department of Biotechnology, Chosun University, 501−759 Gwangju, ) , Bocedi, Alessio (Department of Biochemical Sciences “A. Rossi Fanelli”, Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome,) , Massoud, Renato , Park, Yoonkyung , Mangoni, Maria Luisa , Stella, Lorenzo
    ACS chemical biology v.12 no.1 ,pp. 52 - 56 , 2017 , 1554-8929 ,

    초록

    Host-defense peptides (HDPs) are promising compounds against multidrug-resistant microbes. In vitro, their bactericidal and toxic concentrations are significantly different, but this might be due to the use of separate assays, with different cell densities. For experiments with a single cell type, the cell-density dependence of the active concentration of the DNS-PMAP23 HDP could be predicted based on the water/cell-membrane partition equilibrium and exhibited a lower bound at low cell counts. On the basis of these data, in the simultaneous presence of both bacteria and an excess of human cells, one would expect no significant toxicity, but also inhibition of the bactericidal activity due to peptide sequestration by host cells. However, this inhibition did not take place in assays with mixed cell populations, showing that for the HDP esculentin-la(1-21)NH2, a range of bactericidal, nontoxic concentrations exists and confirming the effective selectivity of HDPs. Mixed-cell assays might be necessary to effectively asses HDP selectivity.

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  2. [해외논문]   Probing the Binding Interfaces of Histone-Aptamer by Photo Cross-Linking Mass Spectrometry   SCIE

    Lu, Congcong (Department of Chemistry, Nankai University, Tianjin 300071, ) , Tian, Shanshan (Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, ) , Zhai, Guijin (Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, ) , Yuan, Zuofei (Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, ) , Li, Yijun (Department of Chemistry, Nankai University, Tianjin 300071, ) , He, Xiwen (Department of Chemistry, Nankai University, Tianjin 300071, ) , Zhang, Yukui (Department of Chemistry, Nankai University, Tianjin 300071, ) , Zhang, Kai (Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biolo)
    ACS chemical biology v.12 no.1 ,pp. 57 - 62 , 2017 , 1554-8929 ,

    초록

    Histone proteins, which could interact with DNA, play important roles in the regulation of chromatin structures, transcription, and other DNA-based biological processes. Here, we developed a novel aptamer-based probe for the analysis of histone H4-aptamer interfaces. This probe contains a DNA sequence for specific recognition of histone H4, a biotin tag for affinity enrichment, an aryl azide photoactive group for cross-linking and a cleavable disulfide group to dissociate aptamer from labeled histones. We successfully achieved specific enrichment of histone H4 and further developed a new analysis strategy for histone-aptamer interaction by photo cross-linking mass spectrometry. The binding area of histone H4 to aptamer was investigated and discussed for the first time. This strategy exhibits great potential and might further contribute to the understanding of histone–DNA interaction patterns. Graphic Abstract ACS Electronic Supporting Info

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  3. [해외논문]   An Effective Bacterial Fucosidase for Glycoprotein Remodeling   SCIE

    Tsai, Tsung-I (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Li, Shiou-Ting (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Liu, Chiu-Ping (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Chen, Karen Y. (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Shivatare, Sachin S. (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Lin, Chin-Wei (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Liao, Shih-Fen (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Lin, Chih-Wei (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Hsu, Tsui-Ling (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Wu, Ying-Ta (Genomics Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 115, ) , Tsai, Ming-Hung (CHO Pharma Inc., Taipei 11503, ) , Lai, Meng-Yu (CHO Pharma Inc., Taipei 11503, ) , Lin, Nan-Horng (CHO Pharma Inc) , Wu, Chung-Yi , Wong, Chi-Huey
    ACS chemical biology v.12 no.1 ,pp. 63 - 72 , 2017 , 1554-8929 ,

    초록

    Fucose is an important component of many oligo- and polysaccharide structures as well as glycoproteins and glycolipids, which are often associated with a variety of physiological processes ranging from fertilization, embryogenesis, signal transduction, and disease progression, such as rheumatoid arthritis, inflammation, and cancer. The enzyme α- l -fucosidase is involved in the cleavage of the fucosidic bond in glycans and glycoconjugates, particularly the Fuc-α-1,2-Gal, Fuc-α-1,3/4-GlcNAc, and Fuc-α-1,6-GlcNAc linkages. Here, we report a highly efficient fucosidase, designated as BfFucH identified from a library of bacterial glycosidases expressed in E. coli from the CAZy database, which is capable of hydrolyzing the aforementioned fucosidic linkages, especially the α-1,6-linkage from the N-linked Fuc-α-1,6-GlcNAc residue on glycoproteins. Using BfFucH coupled with endoglycosidases and the emerging glycosynthases allows glycoengineering of IgG antibodies to provide homogeneous glycoforms with well-defined glycan structures and optimal effector functions. Graphic Abstract ACS Electronic Supporting Info

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  4. [해외논문]   Structure Based Substrate Specificity Analysis of Heparan Sulfate 6-O-Sulfotransferases   SCIE

    Xu, Yongmei (Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, ) , Moon, Andrea F. (Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, ) , Xu, Shuqin (Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, ) , Krahn, Juno M. (Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, ) , Liu, Jian (Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, ) , Pedersen, Lars C. (Genome Integrity and Structural Biology Laboratory, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709,)
    ACS chemical biology v.12 no.1 ,pp. 73 - 82 , 2017 , 1554-8929 ,

    초록

    Heparan sulfate (HS) is a sulfated polysaccharide exhibiting essential physiological functions. HS 6- O -sulfotransferase (6-OST) transfers a sulfo group to the 6-OH position of glucosamine units to confer a variety of HS biological activities. There are three different isoforms of 6-OST in the human genome. Here, we report crystal structures of the ternary complex of 6-OST with the sulfo donor analog 3′-phosphoadenosine 5′-phosphate and three different oligosaccharide substrates at 1.95 to 2.1 A resolutions. Structural and mutational analyses reveal amino acid residues that contribute to catalysis and substrate recognition of 6-OST. Unexpectedly, the structures reveal 6-OST engages HS in a completely different orientation than other HS sulfotransferases and sheds light on the basic HS requirements for specificity. These findings also contribute structural information to understand mutations in human 6-OST isoform 1 associated with the human genetic disease idiopathic hypogonadotropic hypogonadism characterized by incomplete or lack of puberty. Graphic Abstract ACS Electronic Supporting Info

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  5. [해외논문]   Activation Pathway of a Nucleoside Analog Inhibiting Respiratory Syncytial Virus Polymerase   SCIE

    Jordan, Paul C. , Stevens, Sarah K. , Tam, Yuen , Pemberton, Ryan P. , Chaudhuri, Shuvam , Stoycheva, Antitsa D. , Dyatkina, Natalia , Wang, Guangyi , Symons, Julian A. , Deval, Jerome , Beigelman, Leo
    ACS chemical biology v.12 no.1 ,pp. 83 - 91 , 2017 , 1554-8929 ,

    초록

    Human respiratory syncytial virus (RSV) is a negative-sense RNA virus and a significant cause of respiratory infection in infants and the elderly. No effective vaccines or antiviral therapies are available for the treatment of RSV. ALS-8176 is a first-in-class nucleoside prodrug inhibitor of RSV replication currently under clinical evaluation. ALS-8112, the parent molecule of ALS-8176, undergoes intracellular phosphorylation, yielding the active 5′-triphosphate metabolite. The host kinases responsible for this conversion are not known. Therefore, elucidation of the ALS-8112 activation pathway is key to further understanding its conversion mechanism, particularly given its potent antiviral effects. Here, we have identified the activation pathway of ALS-8112 and show it is unlike other antiviral cytidine analogs. The first step, driven by deoxycytidine kinase (dCK), is highly efficient, while the second step limits the formation of the active 5′-triphosphate species. ALS-8112 is a 2′- and 4′-modified nucleoside analog, prompting us to investigate dCK recognition of other 2′- and 4′-modified nucleosides. Our biochemical approach along with computational modeling contributes to an enhanced structure–activity profile for dCK. These results highlight an exciting potential to optimize nucleoside analogs based on the second activation step and increased attention toward nucleoside diphosphate and triphosphate prodrugs in drug discovery. Graphic Abstract ACS Electronic Supporting Info

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  6. [해외논문]   Complete Tetrasaccharide Repeat Unit Biosynthesis of the Immunomodulatory Bacteroides fragilis Capsular Polysaccharide A   SCIE

    Sharma, Sunita , Erickson, Katelyn M. , Troutman, Jerry M.
    ACS chemical biology v.12 no.1 ,pp. 92 - 101 , 2017 , 1554-8929 ,

    초록

    Capsular polysaccharide A (CPSA) is a four-sugar repeating unit polymer found on the surface of the gut symbiont Bacteroides fragilis that has therapeutic potential in animal models of autoimmune disorders. This therapeutic potential has been credited to its zwitterionic character derived from a positively charged N-acetyl-4-aminogalactosamine (AADGal) and a negatively charged 4,6-O-pyruvylated galactose (PyrGal). In this report, using a fluorescent polyisoprenoid chemical probe, the complete enzymatic assembly of the CPSA tetrasaccharide repeat unit is achieved. The proposed pyruvyltransferase, WcfO; galactopyranose mutase, WcfM; and glycosyltransferases, WcfP and WcfN, encoded by the CPSA biosynthesis gene cluster were heterologously expressed and functionally characterized. Pyruvate modification, catalyzed by WcfO, was found to occur on galactose of the polyisoprenoid-linked disaccharide (AADGal-Gal), and did not occur on galactose linked to uridine diphosphate (UDP) or a set of nitrophenyl-galactose analogues. This pyruvate modification was also found to be required for the incorporation of the next sugar in the pathway N-acetylgalactosamine (GalNAc) by the glycosyltransferase WcfP. The pyruvate acetal modification of a galactose has not been previously explored in the context of a polysaccharide biosynthesis pathway, and this work demonstrates the importance of this modification to repeat unit assembly. Upon production of the polyisoprenoid-linked AADGal-PyrGal-GalNAc, the proteins WcfM and WcfN were found to work in concert to form the final tetrasaccharide, where WcfM formed UDP-galactofuranose (Gal f ) and WcfN transfers Gal f to the AADGal-PyrGal-GalNAc. This work demonstrates the first enzymatic assembly of the tetrasaccharide repeat unit of CPSA in a sequential single pot reaction. Graphic Abstract ACS Electronic Supporting Info

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  7. [해외논문]   Targeting NF-κB p65 with a Helenalin Inspired Bis-electrophile   SCIE

    Widen, John C. , Kempema, Aaron M. , Villalta, Peter W. , Harki, Daniel A.
    ACS chemical biology v.12 no.1 ,pp. 102 - 113 , 2017 , 1554-8929 ,

    초록

    The canonical NF-κB signaling pathway is a mediator of the cellular inflammatory response and a target for developing therapeutics for multiple human diseases. The furthest downstream proteins in the pathway, the p50/p65 transcription factor heterodimer, have been recalcitrant toward small molecule inhibition despite the substantial number of compounds known to inhibit upstream proteins in the activation pathway. Given the roles of many of these upstream proteins in multiple biochemical pathways, targeting the p50/p65 heterodimer offers an opportunity for enhanced on-target specificity. Toward this end, the p65 protein presents two nondisulfide cysteines, Cys38 and Cys120, at its DNA-binding interface that are amenable to targeting by covalent molecules. The natural product helenalin, a sesquiterpene lactone, has been previously shown to target Cys38 on p65 and ablate its DNA-binding ability. Using helenalin as inspiration, simplified helenalin analogues were designed, synthesized, and shown to inhibit induced canonical NF-κB signaling in cell culture. Moreover, two simplified helenalin probes were proficient at forming covalent protein adducts, binding to Cys38 on recombinant p65, and targeting p65 in HeLa cells without engaging canonical NF-κB signaling proteins IκBα, p50, and IKKα/β. These studies further support that targeting the p65 transcription factor–DNA interface with covalent small molecule inhibitors is a viable approach toward regulating canonical NF-κB signaling. Graphic Abstract ACS Electronic Supporting Info

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  8. [해외논문]   Inversion of Extender Unit Selectivity in the Erythromycin Polyketide Synthase by Acyltransferase Domain Engineering   SCIE

    Koryakina, Irina (Department of Chemistry, NC State University, Raleigh, North Carolina 27695-8204, ) , Kasey, Christian (Department of Chemistry, NC State University, Raleigh, North Carolina 27695-8204, ) , McArthur, John B. (Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, ) , Lowell, Andrew N. (Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, ) , Chemler, Joseph A. (Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, ) , Li, Shasha (Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, ) , Hansen, Douglas A. (Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, ) , Sherman, David H. (Department of Chemistry, NC State University, Raleigh, North Carolina 27695-8204,) , Williams, Gavin J.
    ACS chemical biology v.12 no.1 ,pp. 114 - 123 , 2017 , 1554-8929 ,

    초록

    Acyltransferase (AT) domains of polyketide synthases (PKSs) select extender units for incorporation into polyketides and dictate large portions of the structures of clinically relevant natural products. Accordingly, there is significant interest in engineering the substrate specificity of PKS ATs in order to site-selectively manipulate polyketide structure. However, previous attempts to engineer ATs have yielded mutant PKSs with relaxed extender unit specificity, rather than an inversion of selectivity from one substrate to another. Here, by directly screening the extender unit selectivity of mutants from active site saturation libraries of an AT from the prototypical PKS, 6-deoxyerythronolide B synthase, a set of single amino acid substitutions was discovered that dramatically impact the selectivity of the PKS with only modest reductions of product yields. One particular substitution (Tyr189Arg) inverted the selectivity of the wild-type PKS from its natural substrate toward a non-natural alkynyl-modified extender unit while maintaining more than twice the activity of the wild-type PKS with its natural substrate. The strategy and mutations described herein form a platform for combinatorial biosynthesis of site-selectively modified polyketide analogues that are modified with non-natural and non-native chemical functionality. Graphic Abstract ACS Electronic Supporting Info

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  9. [해외논문]   Genome Mining of Amino Group Carrier Protein-Mediated Machinery: Discovery and Biosynthetic Characterization of a Natural Product with Unique Hydrazone Unit   SCIE

    Matsuda, Kenichi (Biotechnology Research Center, The University of Tokyo, Tokyo 133-8657, ) , Hasebe, Fumihito (Biotechnology Research Center, The University of Tokyo, Tokyo 133-8657, ) , Shiwa, Yuh (Genome Research Center, NODAI Research Institute, Tokyo University of Agriculture, Tokyo 156-8502, ) , Kanesaki, Yu (Genome Research Center, NODAI Research Institute, Tokyo University of Agriculture, Tokyo 156-8502, ) , Tomita, Takeo (Biotechnology Research Center, The University of Tokyo, Tokyo 133-8657, ) , Yoshikawa, Hirofumi (Genome Research Center, NODAI Research Institute, Tokyo University of Agriculture, Tokyo 156-8502, ) , Shin-ya, Kazuo (National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064 ) , Kuzuyama, Tomohisa (Biotechnology Research Center, The University of Tokyo, Tokyo 133-8657, ) , Nishiyama, Makoto (Biotechnology Research Center, The University of Tokyo, Tokyo 133-8657,)
    ACS chemical biology v.12 no.1 ,pp. 124 - 131 , 2017 , 1554-8929 ,

    초록

    We recently revealed that a Streptomyces strain possesses the gene encoding amino group carrier protein (AmCP). AmCP is involved in the biosynthesis of a previously unidentified nonproteinogenic amino acid, (2 S ,6 R )-diamino-(5 R ,7)-dihydroxy-heptanoic acid (DADH), which is a core compound for the synthesis of the dipeptide-containing novel natural product vazabitide A. We used polymerase chain reaction (PCR) screening to investigate the diversity of the biosynthetic machinery that uses AmCP; the results revealed that genes encoding AmCP are widely distributed among actinomycetes. The heterologous expression of the AmCP-containing gene cluster from Streptomyces sp. SoC090715LN-17 led to the discovery of s56-p1, a novel natural product. The structure of s56-p1 was determined by spectroscopic analysis; the results revealed that s56-p1 has a putative DADH-derived molecule as the core and also possesses a unique hydrazone unit that is rarely observed in natural products. Our results pave the way for investigations of unexploited AmCP-mediated biosynthesis routes among actinomycetes and of the biosynthetic mechanism of the unique hydrazone unit. Graphic Abstract ACS Electronic Supporting Info

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  10. [해외논문]   Phenotypic Screen for Cardiac Regeneration Identifies Molecules with Differential Activity in Human Epicardium-Derived Cells versus Cardiac Fibroblasts   SCIE

    Paunovic, Amalia I. (Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, Cheshire, ) , Drowley, Lauren (Discovery Sciences, AstraZeneca R&D Darwin, 310 Milton Science Park, Milton Rd., Cambridge, CB4 0WG, ) , Nordqvist, Anneli (Molecular Cell Biology, Leiden University Medical Center, Leiden,) , Ericson, Elke , Mouchet, Elizabeth , Jonebring, Anna , Grö , nberg, Gunnar , Kvist, Alexander J. , Engkvist, Ola , Brown, Martin R. , Gedda, Karin , Goumans, Marie-José , , Wang, Qing-Dong , Plowright, Alleyn T.
    ACS chemical biology v.12 no.1 ,pp. 132 - 141 , 2017 , 1554-8929 ,

    초록

    Activation and proliferation of resident cardiac progenitor cells has therapeutic potential to repair the heart after injury. However, research has been impeded by a lack of well-defined and characterized cell sources and difficulties in translation to screening platforms. Here, we describe the development, validation, and use of a 384-well phenotypic assay in primary human epicardium-derived cells (EPDCs) to identify compounds that induce proliferation while maintaining the progenitor phenotype. Using this assay, we screened 7400 structurally diverse compounds where greater than 90% are biologically annotated and known to modulate a broad range of biological targets. From the primary screen, we identified and validated hits and expanded upon the lead molecules of interest. A counterscreen was developed in human cardiac fibroblasts to filter out compounds with a general proliferative effect, after which the activity of selected molecules was confirmed across multiple EPDC donors. To further examine the mechanism of action of compounds with annotated targets, we performed knockdown experiments to understand whether a single known target was responsible for the proliferative effect, confirming results with protein expression and activity assays. Here, we were able to show that the annotated targets of compounds of interest were not responsible for the proliferative effect, which highlights potential differences in cell types and signaling pathways and possible polypharmacology. These studies demonstrate the feasibility of using relevant human primary cells in a phenotypic screen to identify compounds as novel biological tools and starting points for drug discovery projects, and we disclose the first small molecules to proliferate human primary EPDCs. Graphic Abstract ACS Electronic Supporting Info

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