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101.
Franciskovich JB Masters JJ Tinsley JM Craft TJ Froelich LL Gifford-Moore DS Klimkowski VJ Smallwood JK Smith GF Smith T Towner RR Weir LC Wiley MR 《Bioorganic & medicinal chemistry letters》2005,15(21):4838-4841
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT). 相似文献
102.
Beadle CD Boot J Camp NP Dezutter N Findlay J Hayhurst L Masters JJ Penariol R Walter MW 《Bioorganic & medicinal chemistry letters》2005,15(20):4432-4437
A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and advanced intermediates for SAR expansion. 相似文献
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104.
Masters BS 《Biochemical and biophysical research communications》2005,338(1):507-519
This mini-review will reflect the perspective of its author on two fields of research, which have merged as the result of the insights of investigators whose work has influenced both areas immeasurably. It cannot be overlooked, however, that the research activities of many during a period of over five decades have produced the chemical and biological bases for the exciting discoveries now encompassing the cytochromes P450 and their redox partners, and the three isoforms of nitric oxide synthase as they function in their respective biological milieux. Following the remarkable discovery that, indeed, molecular oxygen can be adducted to organic molecules by enzymatic systems and that such processes require a supply of reducing equivalents, it is the purpose of this review to provide a chart, with some of its detours, of the road that followed in the pursuit of interesting biological phenomena involving these two major oxygenation systems. It is not intended to be a balanced review and apologies must be offered in advance to those whose contributions may be overlooked or simply were not directly germane to the development of the author's journey. 相似文献
105.
Eggert S Paliga K Soba P Evin G Masters CL Weidemann A Beyreuther K 《The Journal of biological chemistry》2004,279(18):18146-18156
Amyloid precursor protein (APP) processing is of major interest in Alzheimer's disease research, since sequential cleavages by beta- and gamma-secretase lead to the formation of the 4-kDa amyloid Abeta protein peptide that accumulates in Alzheimer's disease brain. The processing of APP involves proteolytic conversion by different secretases leading to alpha-, beta-, gamma-, delta-, and epsilon-cleavages. Since modulation of these cleavages represents a rational therapeutic approach to control amyloid formation, its interference with the processing of the members of the APP gene family is of considerable importance. By using C-terminally tagged constructs of APLP-1 and APLP-2 and the untagged proteins, we have characterized their proteolytic C-terminal fragments produced in stably transfected SH-SY5Y cells. Pharmacological manipulation with specific protease inhibitors revealed that both homologues are processed by alpha- and gamma-secretase-like cleavages, and that their intracellular domains can be released by cleavage at epsilon-sites. APLP-2 processing appears to be the most elaborate and to involve alternative cleavage sites. We show that APLP-1 is the only member of the APP gene family for which processing can be influenced by N-glycosylation. Additionally, we were able to detect p3-like fragments of APLP-1 and p3-like and Abeta-like fragments of APLP-2 in the media of stably transfected SH-SY5Y cells. 相似文献
106.
Ciccotosto GD Tew D Curtain CC Smith D Carrington D Masters CL Bush AI Cherny RA Cappai R Barnham KJ 《The Journal of biological chemistry》2004,279(41):42528-42534
The amyloid beta peptide (Abeta) is toxic to neuronal cells, and it is probable that this toxicity is responsible for the progressive cognitive decline associated with Alzheimer's disease. However, the nature of the toxic Abeta species and its precise mechanism of action remain to be determined. It has been reported that the methionine residue at position 35 has a pivotal role to play in the toxicity of Abeta. We examined the effect of mutating the methionine to valine in Abeta42 (AbetaM35V). The neurotoxic activity of AbetaM35V on primary mouse neuronal cortical cells was enhanced, and this diminished cell viability occurred at an accelerated rate compared with Abeta42. AbetaM35V binds Cu2+ and produces similar amounts of H2O2 as Abeta42 in vitro, and the neurotoxic activity was attenuated by the H2O2 scavenger catalase. The increased toxicity of AbetaM35V was associated with increased binding of this mutated peptide to cortical cells. The M35V mutation altered the interaction between Abeta and copper in a lipid environment as shown by EPR analysis, which indicated that the valine substitution made the peptide less rigid in the bilayer region with a resulting higher affinity for the bilayer. Circular dichroism spectroscopy showed that both Abeta42 and AbetaM35V displayed a mixture of alpha-helical and beta-sheet conformations. These findings provide further evidence that the toxicity of Abeta is regulated by binding to neuronal cells. 相似文献
107.
CXC chemokine ligand 10 controls viral infection in the central nervous system: evidence for a role in innate immune response through recruitment and activation of natural killer cells 下载免费PDF全文
Trifilo MJ Montalto-Morrison C Stiles LN Hurst KR Hardison JL Manning JE Masters PS Lane TE 《Journal of virology》2004,78(2):585-594
How chemokines shape the immune response to viral infection of the central nervous system (CNS) has largely been considered within the context of recruitment and activation of antigen-specific lymphocytes. However, chemokines are expressed early following viral infection, suggesting an important role in coordinating innate immune responses. Herein, we evaluated the contributions of CXC chemokine ligand 10 (CXCL10) in promoting innate defense mechanisms following coronavirus infection of the CNS. Intracerebral infection of RAG1(-/-) mice with a recombinant CXCL10-expressing murine coronavirus (mouse hepatitis virus) resulted in protection from disease and increased survival that correlated with a significant increase in recruitment and activation of natural killer (NK) cells within the CNS. Accumulation of NK cells resulted in a reduction in viral titers that was dependent on gamma interferon secretion. These results indicate that CXCL10 expression plays a pivotal role in defense following coronavirus infection of the CNS by enhancing innate immune responses. 相似文献
108.
The 3' cis-acting genomic replication element of the severe acute respiratory syndrome coronavirus can function in the murine coronavirus genome 下载免费PDF全文
The 3' untranslated region (3' UTR) of the genome of the severe acute respiratory syndrome coronavirus can functionally replace its counterpart in the prototype group 2 coronavirus mouse hepatitis virus (MHV). By contrast, the 3' UTRs of representative group 1 or group 3 coronaviruses cannot operate as substitutes for the MHV 3' UTR. 相似文献
109.
110.
Martin P. Boland Claire R. Hatty Frances Separovic Andrew F. Hill Deborah J. Tew Kevin J. Barnham Cathryn L. Haigh Michael James Colin L. Masters Steven J. Collins 《The Journal of biological chemistry》2010,285(42):32282-32292
Although the N terminus of the prion protein (PrPC) has been shown to directly associate with lipid membranes, the precise determinants, biophysical basis, and functional implications of such binding, particularly in relation to endogenously occurring fragments, are unresolved. To better understand these issues, we studied a range of synthetic peptides: specifically those equating to the N1 (residues 23–110) and N2 (23–89) fragments derived from constitutive processing of PrPC and including those representing arbitrarily defined component domains of the N terminus of mouse prion protein. Utilizing more physiologically relevant large unilamellar vesicles, fluorescence studies at synaptosomal pH (7.4) showed absent binding of all peptides to lipids containing the zwitterionic headgroup phosphatidylcholine and mixtures containing the anionic headgroups phosphatidylglycerol or phosphatidylserine. At pH 5, typical of early endosomes, quartz crystal microbalance with dissipation showed the highest affinity binding occurred with N1 and N2, selective for anionic lipid species. Of particular note, the absence of binding by individual peptides representing component domains underscored the importance of the combination of the octapeptide repeat and the N-terminal polybasic regions for effective membrane interaction. In addition, using quartz crystal microbalance with dissipation and solid-state NMR, we characterized for the first time that both N1 and N2 deeply insert into the lipid bilayer with minimal disruption. Potential functional implications related to cellular stress responses are discussed. 相似文献