排序方式: 共有17条查询结果,搜索用时 0 毫秒
11.
Alistair OBrien Stephen P. Andrews Asma H. Baig Andrea Bortolato Alastair J.H. Brown Giles A. Brown Sue H. Brown John A. Christopher Miles Congreve Robert M. Cooke Chris De Graaf James C. Errey Charlotte Fieldhouse Ali Jazayeri Fiona H. Marshall Jonathan S. Mason Juan Carlos Mobarec Krzysztof Okrasa Malcolm Weir 《Bioorganic & medicinal chemistry letters》2019,29(20):126611
A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C3476.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R. 相似文献
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Daniel Krska Ravikiran Ravulapalli Robert J. Fieldhouse Miguel R. Lugo A. Rod Merrill 《The Journal of biological chemistry》2015,290(3):1639-1653
C3larvin toxin was identified by a bioinformatic strategy as a putative mono-ADP-ribosyltransferase and a possible virulence factor from Paenibacillus larvae, which is the causative agent of American Foulbrood in honey bees. C3larvin targets RhoA as a substrate for its transferase reaction, and kinetics for both the NAD+ (Km = 34 ± 12 μm) and RhoA (Km = 17 ± 3 μm) substrates were characterized for this enzyme from the mono-ADP-ribosyltransferase C3 toxin subgroup. C3larvin is toxic to yeast when expressed in the cytoplasm, and catalytic variants of the enzyme lost the ability to kill the yeast host, indicating that the toxin exerts its lethality through its enzyme activity. A small molecule inhibitor of C3larvin enzymatic activity was discovered called M3 (Ki = 11 ± 2 μm), and to our knowledge, is the first inhibitor of transferase activity of the C3 toxin family. C3larvin was crystallized, and its crystal structure (apoenzyme) was solved to 2.3 Å resolution. C3larvin was also shown to have a different mechanism of cell entry from other C3 toxins. 相似文献
13.
Effect of carbachol or histamine stimulation on rat gastric membranes enriched in (H+-K+)-ATPase 总被引:2,自引:0,他引:2
We have examined histamine- or carbachol-induced changes in rat gastric membranes enriched in K+-stimulated ATPase. Stimulation of secretion by both secretagogues in vivo produced a class of microsomal membranes which exhibited valinomycin-independent, KCl-dependent H+ transport. In contrast, membrane vesicles isolated from cimetidine inhibited resting mucosa exhibited largely the ionophore-dependent H+ transport. In addition, only in the carbachol-stimulated membranes a portion of the ionophore-independent H+ transport was refractory to cimetidine pretreatment. The gastric microsomal membranes were resolved into light and heavy fractions by centrifugation over isotonic 2H2O media. The ionophore-independent H+ transport was almost exclusively associated with the heavy microsomal fraction while the ionophore-dependent H+ transport was detected in the light fraction. Also, these fractions were considerably different from each other in their appearance in electron micrographs and SDS gel electrophoresis patterns. Secretagogue stimulation increased the population of the heavy microsomal membrane vesicles exhibiting the valinomycin-independent, K+-dependent H+ transport and their overall content of K+-stimulated ATPase. Cimetidine treatment, on the other hand, increased the ATPase activity associated with the light microsomes, and produced the heavy microsomal membranes showing only a marginal degree of the ionophore independent H+ accumulation, even though they were very similar to the carbachol-stimulated heavy membranes in the specific activity of K+-stimulated ATPase. SDS gel patterns and appearance in electron micrograph. These observations suggest that activation of secretion involves at least two distinctive events; transformation of the light to the heavy gastric membranes containing a K+-dependent H+ pump and an increased KCl permeability in the latter. 相似文献
14.
Sime M Allan AC Chapman P Fieldhouse C Giblin GM Healy MP Lambert MH Leesnitzer LM Lewis A Merrihew RV Rutter RA Sasse R Shearer BG Wilson TM Xu RX Virley DJ 《Bioorganic & medicinal chemistry letters》2011,21(18):5568-5572
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described. 相似文献
15.
Allan AC Billinton A Brown SH Chowdhury A Eatherton AJ Fieldhouse C Giblin GM Goldsmith P Hall A Hurst DN Naylor A Rawlings DA Sime M Scoccitti T Theobald PJ 《Bioorganic & medicinal chemistry letters》2011,21(14):4343-4348
We describe the discovery and optimization of a novel series of benzofuran EP1 antagonists, leading to the identification of 26d, a novel nonacidic EP1 antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain. 相似文献
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17.
Zachari Turgeon Dawn White René Jørgensen Danielle Visschedyk Robert J. Fieldhouse Dev Mangroo & A. Rod Merrill 《FEMS microbiology letters》2009,300(1):97-106
The emergence of bacterial antibiotic resistance poses a significant challenge in the pursuit of novel therapeutics, making new strategies for drug discovery imperative. We have developed a yeast growth-defect phenotypic screen to help solve this current dilemma. This approach facilitates the identification and characterization of a new diphtheria toxin (DT) group, ADP-ribosyltransferase toxins from pathogenic bacteria. In addition, this assay utilizes Saccharomyces cerevisiae , a reliable model for bacterial toxin expression, to streamline the identification and characterization of new inhibitors against this group of bacterial toxins that may be useful for antimicrobial therapies. We show that a mutant of the elongation factor 2 target protein in yeast, G701R, confers resistance to all DT group toxins and recovers the growth-defect phenotype in yeast. We also demonstrate the ability of a potent small-molecule toxin inhibitor, 1,8-naphthalimide (NAP), to alleviate the growth defect caused by toxin expression in yeast. Moreover, we determined the crystal structure of the NAP inhibitor–toxin complex at near-atomic resolution to provide insight into the inhibitory mechanism. Finally, the NAP inhibitor shows therapeutic protective effects against toxin invasion of mammalian cells, including human lung cells. 相似文献