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Inhibitor Compounds (inhibitor + compound)

Distribution by Scientific Domains

Life Sciences	50%

Selected Abstracts

Human GCIP interacts with CT847, a novel Chlamydia trachomatis type III secretion substrate, and is degraded in a tissue-culture infection model

CELLULAR MICROBIOLOGY, Issue 10 2007
Blandine Chellas-Géry
Summary The obligate intracellular bacterium Chlamydia trachomatis occupies a parasitophorous vacuole and employs a type III secretion mechanism to translocate host-interactive proteins. These proteins most likely contribute to pathogenesis through modulation of host cell mechanisms crucial for the establishment and maintenance of a permissive intracellular environment. Using a surrogate Yersinia type III secretion system (T3SS), we have identified the conserved gene product CT847 as a chlamydial T3SS substrate. Yeast two-hybrid studies using CT847 as bait to screen a HeLa cell cDNA library identified an interaction with mammalian Grap2 cyclin D- interacting protein (GCIP). Immunoblot analyses of C. trachomatis -infected HeLa cells showed that GCIP levels begin to decrease (as compared with mock-infected HeLa cells) between 8 h and 12 h post infection. GCIP was virtually undetectable in 24 h time point material. This decrease was inhibited by proteasome inhibitors lactacystin and MG-132, and the T3SS inhibitor Compound 1. CT847 was detectible in purified reticulate body but not elementary body lysates, and reverse transcription polymerase chain reaction (RT-PCR) expression analyses indicate a mid-cycle expression pattern. Both of these findings are consistent with CT847 contributing to the observed effect on GCIP. Given the established roles of GCIP, we believe that we have discovered a novel C. trachomatis antihost protein whose activity is relevant to chlamydial pathogenesis. [source]

Effects of motilin on intracellular free calcium in cultured smooth muscle cells from the antrum of neonatal rats

ACTA PHYSIOLOGICA, Issue 1 2010
P. Fang
Abstract Aim:, The aim of this study was to determine the effects of motilin on [Ca2+]i regulation and its underlying molecular mechanism in cultured antral smooth muscle cells (ASMCs). Methods:, Antral cells were isolated and cultured from neonatal rats, and then the [Ca2+]i in these cells was evaluated by calcium fluorescent probe Fluo-3/AM on a laser scanning confocal microscope. Results:, We show that motilin dose-dependently increased [Ca2+]i concentration in cultured ASMCs. Pre-incubation of cells with either the calcium antagonist verapamil (10,5 mol L,1) or the calcium chelator Egtazic (EGTA, 0.1 mmol L,1) significantly suppressed motilin (10,6 mol L,1) induced [Ca2+]i increase as indicated by fluorescent intensity. Interestingly, after mixing with the non-selective intracellular calcium release blocker TMB-8 (10,5 mol L,1), guanosine triphosphate regulatory protein antagonist NEM (10,5 mol L,1), phospholipase C (PLC) inhibitor compound 48/80 (1.2 ,g mL,1) and ryanodine at high concentration (10,5 mol L,1), the motilin-induced [Ca2+]i increase was only partially blocked. The protein kinase C inhibitor d -sphingosine (10,6 mol L,1), however, did not show any inhibitory effect on motilin-induced [Ca2+]i elevation. Conclusions:, Our study suggests that motilin-stimulated [Ca2+]i elevation in ASMCs is probably due to sustained extracellular Ca2+ influx and Ca2+ release from Ca2+ stores via inositol tris-phosphate receptors and ryanodine receptors. Specifically, motilin-induced [Ca2+]i release is accompanied with guanosine triphosphate-binding protein-coupled receptor,PLC,inositol tris-phosphate signalling cascades. [source]

Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosis

FEBS JOURNAL, Issue 20 2006
Ekaterina Morgunova
Recently published genomic investigations of the human pathogen Mycobacterium tuberculosis have revealed that genes coding the proteins involved in riboflavin biosynthesis are essential for the growth of the organism. Because the enzymes involved in cofactor biosynthesis pathways are not present in humans, they appear to be promising candidates for the development of therapeutic drugs. The substituted purinetrione compounds have demonstrated high affinity and specificity to lumazine synthase, which catalyzes the penultimate step of riboflavin biosynthesis in bacteria and plants. The structure of M. tuberculosis lumazine synthase in complex with five different inhibitor compounds is presented, together with studies of the binding reactions by isothermal titration calorimetry. The inhibitors showed the association constants in the micromolar range. The analysis of the structures demonstrated the specific features of the binding of different inhibitors. The comparison of the structures and binding modes of five different inhibitors allows us to propose the ribitylpurinetrione compounds with C4,C5 alkylphosphate chains as most promising leads for further development of therapeutic drugs against M. tuberculosis. [source]

Genotype-dependent sensitivity of hepatitis C virus to inhibitors of the p7 ion channel,

HEPATOLOGY, Issue 6 2008
Stephen Griffin
The hepatitis C virus (HCV) p7 protein plays a critical role during particle formation in cell culture and is required for virus replication in chimpanzees. The discovery that it displayed cation channel activity in vitro led to its classification within the "viroporin" family of virus-coded ion channel proteins, which includes the influenza A virus (IAV) M2 protein. Like M2, p7 was proposed as a potential target for much needed new HCV therapies, and this was supported by our finding that the M2 inhibitor, amantadine, blocked its activity in vitro. Since then, further compounds have been shown to inhibit p7 function but the relationship between inhibitory effects in vitro and efficacy against infectious virus is controversial. Here, we have sought to validate multiple p7 inhibitor compounds using a parallel approach combining the HCV infectious culture system and a rapid throughput in vitro assay for p7 function. We identify a genotype-dependent and subtype-dependent sensitivity of HCV to p7 inhibitors, in which results in cell culture largely mirror the sensitivity of recombinant protein in vitro; thus building separate sensitivity profiles for different p7 sequences. Inhibition of virus entry also occurred, suggesting that p7 may be a virion component. Second site effects on both cellular and viral processes were identified for several compounds in addition to their efficacy against p7 in vitro. Nevertheless, for some compounds antiviral effects were specific to a block of ion channel function. Conclusion: These data validate p7 inhibitors as prototype therapies for chronic HCV disease. (HEPATOLOGY 2008;48:1779-1790.) [source]