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991.
M Beconi O Aziz K Matthews L Moumné C O'Connell D Yates S Clifton H Pett J Vann L Crowley AF Haughan DL Smith B Woodman GP Bates F Brookfield RW Bürli G McAllister C Dominguez I Munoz-Sanjuan V Beaumont 《PloS one》2012,7(9):e44498
Histone deacetylase (HDAC) inhibitors have received considerable attention as potential therapeutics for a variety of cancers and neurological disorders. Recent publications on a class of pimelic diphenylamide HDAC inhibitors have highlighted their promise in the treatment of the neurodegenerative diseases Friedreich's ataxia and Huntington's disease, based on efficacy in cell and mouse models. These studies' authors have proposed that the unique action of these compounds compared to hydroxamic acid-based HDAC inhibitors results from their unusual slow-on/slow-off kinetics of binding, preferentially to HDAC3, resulting in a distinctive pharmacological profile and reduced toxicity. Here, we evaluate the HDAC subtype selectivity, cellular activity, absorption, distribution, metabolism and excretion (ADME) properties, as well as the central pharmacodynamic profile of one such compound, HDACi 4b, previously described to show efficacy in vivo in the R6/2 mouse model of Huntington's disease. Based on our data reported here, we conclude that while the in vitro selectivity and binding mode are largely in agreement with previous reports, the physicochemical properties, metabolic and p-glycoprotein (Pgp) substrate liability of HDACi 4b render this compound suboptimal to investigate central Class I HDAC inhibition in vivo in mouse per oral administration. A drug administration regimen using HDACi 4b dissolved in drinking water was used in the previous proof of concept study, casting doubt on the validation of CNS HDAC3 inhibition as a target for the treatment of Huntington's disease. We highlight physicochemical stability and metabolic issues with 4b that are likely intrinsic liabilities of the benzamide chemotype in general. 相似文献
992.
993.
Glucocorticoids (GCs) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to therapy. The high doses of GC required for less responsive patients means a high risk of developing very serious side effects. Variation in sensitivity between individuals can be due to a number of factors. Congenital, generalized GC resistance is very rare, and is due to mutations in the glucocorticoid receptor (GR) gene, the receptor that mediates the cellular effects of GC. A more common problem is acquired GC resistance. This localized, disease-associated GC resistance is a serious therapeutic concern and limits therapeutic response in patients with chronic inflammatory disease. It is now believed that localized resistance can be attributed to changes in the cellular microenvironment, as a consequence of chronic inflammation. Multiple factors have been identified, including alterations in both GR-dependent and -independent signaling downstream of cytokine action, oxidative stress, hypoxia and serum derived factors. The underlying mechanisms are now being elucidated, and are discussed here. Attempts to augment tissue GC sensitivity are predicted to permit safe and effective use of low-dose GC therapy in inflammatory disease. 相似文献
994.
Webber SE Marakovits JT Dragovich PS Prins TJ Zhou R Fuhrman SA Patick AK Matthews DA Lee CA Srinivasan B Moran T Ford CE Brothers MA Harr JE Meador JW Ferre RA Worland ST 《Bioorganic & medicinal chemistry letters》2001,11(20):2683-2686
Novel tripeptidyl C-terminal Michael acceptors with an ester replacement of the P(2)-P(3) amide bond were investigated as irreversible inhibitors of the human rhinovirus (HRV) 3C protease (3CP). When screened against HRV serotype-14 the best compound was shown to have very good 3CP inhibition (k(obs)/[I]=270,000M(-1)s(-1)) and potent in vitro antiviral activity (EC(50)=7.0nM). 相似文献
995.
996.
Over 100 amino acid replacements in human Cu,Zn superoxide dismutase (SOD) are known to cause amyotrophic lateral sclerosis, a gain-of-function neurodegenerative disease that destroys motor neurons. Supposing that aggregates of partially folded states are primarily responsible for toxicity, we determined the role of the structurally important zinc ion in defining the folding free energy surface of dimeric SOD by comparing the thermodynamic and kinetic folding properties of the zinc-free and zinc-bound forms of the protein. The presence of zinc was found to decrease the free energies of a peptide model of the unfolded monomer, a stable variant of the folded monomeric intermediate, and the folded dimeric species. The unfolded state binds zinc weakly with a micromolar dissociation constant, and the folded monomeric intermediate and the native dimeric form both bind zinc tightly, with subnanomolar dissociation constants. Coupled with the strong driving force for the subunit association reaction, the shift in the populations toward more well-folded states in the presence of zinc decreases the steady-state populations of higher-energy states in SOD under expected in vivo zinc concentrations (approximately nanomolar). The significant decrease in the population of partially folded states is expected to diminish their potential for aggregation and account for the known protective effect of zinc. The ∼ 100-fold increase in the rate of folding of SOD in the presence of micromolar concentrations of zinc demonstrates a significant role for a preorganized zinc-binding loop in the transition-state ensemble for the rate-limiting monomer folding reaction in this β-barrel protein. 相似文献
997.
998.
Central role of reverting mutations in HLA associations with human immunodeficiency virus set point 总被引:3,自引:1,他引:2
Matthews PC Prendergast A Leslie A Crawford H Payne R Rousseau C Rolland M Honeyborne I Carlson J Kadie C Brander C Bishop K Mlotshwa N Mullins JI Coovadia H Ndung'u T Walker BD Heckerman D Goulder PJ 《Journal of virology》2008,82(17):8548-8559
Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8+ T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert posttransmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = −0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = −0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses. 相似文献
999.
Davis AM Hagan KA Matthews LA Bajwa G Gill MA Gale M Farrar JD 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(10):6923-6932
CD4(+) T cells directly participate in bacterial clearance through secretion of proinflammatory cytokines. Although viral clearance relies heavily on CD8(+) T cell functions, we sought to determine whether human CD4(+) T cells could also directly influence viral clearance through cytokine secretion. We found that IFN-gamma and TNF-alpha, secreted by IL-12-polarized Th1 cells, displayed potent antiviral effects against a variety of viruses. IFN-gamma and TNF-alpha acted directly to inhibit hepatitis C virus replication in an in vitro replicon system, and neutralization of both cytokines was required to block the antiviral activity that was secreted by Th1 cells. IFN-gamma and TNF-alpha also exerted antiviral effects against vesicular stomatitis virus infection, but in this case, functional type I IFN receptor activity was required. Thus, in cases of vesicular stomatitis virus infection, the combination of IFN-gamma and TNF-alpha secreted by human Th1 cells acted indirectly through the IFN-alpha/beta receptor. These results highlight the importance of CD4(+) T cells in directly regulating antiviral responses through proinflammatory cytokines acting in both a direct and indirect manner. 相似文献
1000.
In Vitis vinifera L. berries, the onset of ripening (known as “veraison”) involves loss of turgor (P) in the mesocarp cells. We hypothesized
that P loss was associated with an accumulation of apoplastic solutes in mesocarp tissue prior to veraison. Apoplastic sap
was extracted from the mesocarp by centrifugation at the appropriate gravity to measure the apoplast solute potential (ΨsA) and assay the sap composition. The ΨsA was about −0.2 MPa early in development, decreased about 1.0 MPa by veraison, and continued to decrease during ripening to
almost −4.0 MPa by the end of berry development. Potassium, malate, tartrate, proline, glucose, fructose, and sucrose were
quantified in apoplastic sap. The calculated contribution of these solutes was about 50% of the total ΨsA preveraison, but increased to about 75% as fructose and glucose accumulated during ripening. The contribution of the estimated
matric potential to apoplast water potential decreased during development and was only 1.5% postveraison. We conclude that
high concentrations of solutes accumulated in the mesocarp apoplast prior to veraison, and that P loss was a direct result
of decreased ΨsA. Because ΨsA decreased before veraison, our findings suggest that apoplast solutes play an important role in the events of cellular metabolism
that lead to the onset of ripening. 相似文献