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Berlin Brandenburg

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  • 1
    In: Nature Biotechnology, 2003, Vol.21(6), p.687
    Description: To realize the promise of genomics-based therapeutics, new methods are needed to accelerate the discovery of small molecules that selectively modulate protein activity. Toward this end, advances in combinatorial synthesis have provided unprecedented access to large compound libraries of considerable structural complexity and diversity, shifting the bottleneck in drug discovery to the development of efficient screens for protein targets. Screening for reversible enzyme inhibitors typically requires extensive target-specific work, including protein expression and purification, as well as the development of specific substrate assays. Here we report a proteomic method for the discovery of reversible enzyme inhibitors that avoids these steps. We show that competitive profiling of a library of candidate serine hydrolase inhibitors in complex proteomes with activity-based chemical probes identifies nanomolar reversible inhibitors of several enzymes simultaneously, including the endocannabinoid-degrading enzyme fatty acid amide hydrolase (FAAH), triacylglycerol hydrolase (TGH) and an uncharacterized membrane-associated hydrolase that lacks known substrates. The strategy tests inhibitors against numerous enzymes in parallel, assigning both potency and selectivity factors to each agent. In this way, promiscuous inhibitors were readily rejected in favor of equally potent compounds with 500-fold or greater selectivity for their targets.
    Keywords: Medicine ; Engineering ; Biology;
    ISSN: 1087-0156
    E-ISSN: 1546-1696
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  • 2
  • 3
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.3259-3259
    Description: Angiopoeitin-2 (Ang2) is released from endothelial cells only in response to stimulus (e.g. wound healing, tumor growth) and facilitates blood vessel sprouting and inhibits pericyte-endothelial cell interaction via Tie2 signaling. Combination of an anti-Ang2 antibody and aflibercept,...
    Keywords: Cell Survival ; Vascular Endothelial Growth Factor ; Ovarian Cancer ; Retina ; Immunotherapy ; Animal Models ; Angiogenesis ; Pericytes ; Wound Healing ; Tumors ; Clinical Trials ; Metastases ; Endothelial Cells ; Antibodies ; Blood Vessels ; Immunoglobulin G ; Cell Interactions ; Xenografts ; Products;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 4
    Language: English
    In: Biochemistry, 18 April 2006, Vol.45(15), pp.4720-6
    Description: N-Acyl ethanolamines (NAEs) constitute a large and diverse class of signaling lipids that includes the endogenous cannabinoid anandamide. Like other lipid transmitters, NAEs are thought to be biosynthesized and degraded on-demand rather than being stored in vesicles prior to signaling. The identification of enzymes involved in NAE metabolism is therefore imperative to achieve a complete understanding of this lipid signaling system and control it for potential therapeutic gain. Recently, an N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) was identified as a candidate enzyme involved in the biosynthesis of NAEs. Here, we describe the generation and characterization of mice with a targeted disruption in the NAPE-PLD gene [NAPE-PLD(-/-) mice]. Brain tissue from NAPE-PLD(-/-) mice showed more than a 5-fold reduction in the calcium-dependent conversion of NAPEs to NAEs bearing both saturated and polyunsaturated N-acyl chains. However, only the former group of NAEs was decreased in level in NAPE-PLD(-/-) brains, and these reductions were most dramatic for NAEs bearing very long acyl chains (〉or=C20). Further studies identified a calcium-independent PLD activity in brains from NAPE-PLD(-/-) mice that accepted multiple NAPEs as substrates, including the anandamide precursor C20:4 NAPE. The illumination of distinct enzymatic pathways for the biosynthesis of long chain saturated and polyunsaturated NAEs suggests a strategy to control the activity of specific subsets of these lipids without globally affecting the function of the NAE family as a whole.
    Keywords: Endocannabinoids ; Cannabinoid Receptor Modulators -- Biosynthesis ; Phospholipase D -- Metabolism
    ISSN: 0006-2960
    E-ISSN: 15204995
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 26 April 2005, Vol.102(17), pp.6195-200
    Description: Organophosphorus (OP) insecticides and chemical warfare agents act primarily by inhibiting acetylcholinesterase. There are many secondary targets for OP toxicants as observed for example with the major insecticide chlorpyrifos and its bioactivated metabolite chlorpyrifos oxon (CPO). Therefore, it was surprising that the predominant mouse brain protein labeled in vitro by [(3)H-ethyl]CPO (1 nM) (designated CPO-binding protein or CPO-BP) is not one of these known OP toxicant targets. CPO-BP is a 50-kDa membrane-bound serine hydrolase measured by derivatization with [(3)H]CPO and SDS/PAGE or filtration binding assay. It appears to undergo rapid diethylphosphorylation by [(3)H]CPO followed by either dephosphorylation and reactivation or aging on loss of an ethyl group. CPO and several other OP toxicants potently inhibit CPO-BP in vivo (i.p., 2 h) (50% inhibition at 2-25 mg/kg) and in vitro (50% inhibition at 8-68 nM). Using three chemical labeling reagents, i.e., [(3)H]CPO and the activity-based proteomic probes fluorophosphonate-biotin and fluorophosphonate-rhodamine, mouse brain CPO-BP is identified as serine hydrolase KIAA1363 of unknown function. Brains from KIAA1363(-/-) mice show greatly reduced levels of CPO labeling and hydrolytic metabolism compared to brains from wild-type mice. KIAA1363 therefore is the principal enzyme for metabolizing low levels of CPO in brain and may play a more general role in detoxification of OP nerve poisons.
    Keywords: Brain -- Enzymology ; Chlorpyrifos -- Analogs & Derivatives ; Neurotoxins -- Pharmacokinetics
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 6
    Language: English
    In: mAbs, 02 November 2015, Vol.7(6), pp.1084-1093
    Description: The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the...
    Keywords: Non-Specific Binding ; Neonatal Fc Receptor (Fcrn) ; Antibody Pharmacokinetics ; Charge Interactions of Iggs ; Target Mediated Disposition ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1942-0862
    E-ISSN: 1942-0870
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  • 7
    Language: English
    In: PLoS ONE, 2008, Vol.3(7), p.e2486
    Description: Phosphoprotein phosphatase 2A (PP2A), a major serine-threonine protein phosphatase in eukaryotes, is an oligomeric protein comprised of structural (A) and catalytic (C) subunits to which a variable regulatory subunit (B) can associate. The C subunit contains a methyl ester post-translational modification on its C-terminal leucine residue, which is removed by a specific methylesterase (PME-1). Methylesterification is thought to control the binding of different B subunits to AC dimers, but little is known about its physiological significance in vivo. ; Here, we show that targeted disruption of the gene causes perinatal lethality in mice, a phenotype that correlates with a virtually complete loss of the demethylated form of PP2A in the nervous system and peripheral tissues. Interestingly, PP2A catalytic activity over a peptide substrate was dramatically reduced in tissues, which also displayed alterations in phosphoproteome content. ; These findings suggest a role for the demethylated form of PP2A in maintenance of enzyme function and phosphorylation networks .
    Keywords: Research Article ; Biochemistry ; Biochemistry -- Cell Signaling And Trafficking Structures
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Journal of Medicinal Chemistry, 02/2000, Vol.43(3), pp.305-341
    ISSN: 0022-2623
    E-ISSN: 1520-4804
    Source: American Chemical Society (via CrossRef)
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  • 9
    Language: English
    In: mAbs, 04 May 2015, Vol.7(3), pp.483-493
    Description: Lowering the isoelectric point (pI) through engineering the variable region or framework of an IgG can improve its exposure and half-life via a reduction in clearance mediated through non-specific interactions. As such, net charge is a potentially important property to consider in developing...
    Keywords: Non-Specific Binding ; Antibody Pharmacokinetics ; Charge Interactions of Iggs ; in Vitro Degradation ; Hek293 Cells ; Cdr Modification ; Fcrn Recycling ; Radiolabel Antibody Biodistribution ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 1942-0862
    E-ISSN: 1942-0870
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  • 10
    Language: English
    In: Journal of Biological Chemistry, 12/07/2001, Vol.276(49), pp.45762-45771
    Description: Recombinant forms of the dengue 2 virus NS3 protease linked to a 40-residue co-factor, corresponding to part of NS2B, have been expressed in Escherichia coli and shown to be active against para-nitroanilide substrates comprising the P6-P1 residues of four substrate cleavage sequences. The enzyme is inactive alone or after the addition of a putative 13-residue co-factor peptide but is active when fused to the 40-residue co-factor, by either a cleavable or a noncleavable glycine linker. The NS4B/NS5 cleavage site was processed most readily, with optimal processing conditions being pH 9, I = 10 mm, 1 mm CHAPS, 20% glycerol. A longer 10-residue peptide corresponding to the NS2B/NS3 cleavage site (P6-P4') was a poorer substrate than the hexapeptide (P6-P1) para-nitroanilide substrate under these conditions, suggesting that the prime side substrate residues did not contribute significantly to protease binding. We also report the first inhibitors of a co-factor-complexed, catalytically active flavivirus NS3 protease. Aprotinin was the only standard serine protease inhibitor to be active, whereas a number of peptide substrate analogues were found to be competitive inhibitors at micromolar concentrations.
    Keywords: Peptides -- Metabolism ; Protease Inhibitors -- Pharmacology ; Viral Nonstructural Proteins -- Metabolism;
    ISSN: 0021-9258
    E-ISSN: 1083-351X
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