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排序方式: 共有270条查询结果,搜索用时 15 毫秒
31.
Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases 总被引:1,自引:0,他引:1
Becker GL Lu Y Hardes K Strehlow B Levesque C Lindberg I Sandvig K Bakowsky U Day R Garten W Steinmetzer T 《The Journal of biological chemistry》2012,287(26):21992-22003
Optimization of our previously described peptidomimetic furin inhibitors was performed and yielded several analogs with a significantly improved activity. The most potent compounds containing an N-terminal 4- or 3-(guanidinomethyl)phenylacetyl residue inhibit furin with K(i) values of 16 and 8 pM, respectively. These analogs inhibit other proprotein convertases, such as PC1/3, PC4, PACE4, and PC5/6, with similar potency, whereas PC2, PC7, and trypsin-like serine proteases are poorly affected. Incubation of selected compounds with Madin-Darby canine kidney cells over a period of 96 h revealed that they exhibit great stability, making them suitable candidates for further studies in cell culture. Two of the most potent derivatives were used to inhibit the hemagglutinin cleavage and viral propagation of a highly pathogenic avian H7N1 influenza virus strain. The treatment with inhibitor 24 (4-(guanidinomethyl)phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide) resulted in significantly delayed virus propagation compared with an inhibitor-free control. The same analog was also effective in inhibiting Shiga toxin activation in HEp-2 cells. This antiviral effect, as well as the protective effect against a bacterial toxin, suggests that inhibitors of furin or furin-like proprotein convertases could represent promising lead structures for future drug development, in particular for the treatment of infectious diseases. 相似文献
32.
Boyle B Fernandez L Laroche J Kukavica-Ibrulj I Mendes CM Hancock RW Levesque RC 《Journal of bacteriology》2012,194(2):529-530
Clinical "superbug" isolates of Pseudomonas aeruginosa were previously observed to be resistant to several antibiotics, including polymyxin B, and/or to have a distinct, reproducible adaptive polymyxin resistance phenotype, identified by observing "skipped" wells (appearance of extra turbid wells) during broth microdilution testing. Here we report the complete assembled draft genome sequences of three such polymyxin resistant P. aeruginosa strains (9BR, 19BR, and 213BR). 相似文献
33.
Chen YY Harris MP Levesque MP Nüsslein-Volhard C Sonawane M 《Mechanisms of development》2012,129(1-4):13-23
In vertebrates, the dorso-ventral (DV) axis is defined by the combinatorial action of localised Wnt, FGF and Nodal signalling along with the antagonizing activities of Chordin and BMP pathways. Our knowledge of the factors that may act in concert with these core pathways to regulate early embryonic patterning is far from complete. Furthermore, while all three germ layers respond to these patterning cues, it is not clear whether in zebrafish the outermost protective epithelium, the enveloping layer (EVL), is also patterned along the DV axis. Here, we have identified a transgenic line driving GFP under a crestin promoter, which specifically labels the dorsal domain of the EVL suggesting heterogeneity in the EVL across the DV axis. Our attempts to understand how the expression from this promoter fragment is regulated specifically in the dorsal domain, have unravelled potential novel players involved in early EVL and embryonic patterning. We show that along with Nodal signalling components, four proteins Sox11b, Sox19b, Snail1a and Max are involved in regulating the size of this EVL domain. However, Chordin-BMP signalling might be dispensable for the dorso-ventral patterning of the EVL. For the first time, this transgenic line unravels the heterogeneity in the EVL and will serve as an important tool in understanding the molecular basis of the DV patterning of the EVL. 相似文献
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Lloyd AJ Gilbey AM Blewett AM De Pascale G El Zoeiby A Levesque RC Catherwood AC Tomasz A Bugg TD Roper DI Dowson CG 《The Journal of biological chemistry》2008,283(10):6402-6417
MurM is an aminoacyl ligase that adds l-serine or l-alanine as the first amino acid of a dipeptide branch to the stem peptide lysine of the pneumococcal peptidoglycan. MurM activity is essential for clinical pneumococcal penicillin resistance. Analysis of peptidoglycan from the highly penicillin-resistant Streptococcus pneumoniae strain 159 revealed that in vivo and in vitro, in the presence of the appropriate acyl-tRNA, MurM(159) alanylated the peptidoglycan epsilon-amino group of the stem peptide lysine in preference to its serylation. However, in contrast, identical analyses of the penicillin-susceptible strain Pn16 revealed that MurM(Pn16) activity supported serylation more than alanylation both in vivo and in vitro. Interestingly, both MurM(Pn16) acylation activities were far lower than the alanylation activity of MurM(159). The resulting differing stem peptide structures of 159 and Pn16 were caused by the profoundly greater catalytic efficiency of MurM(159) compared with MurM(Pn16) bought about by sequence variation between these enzymes and, to a lesser extent, differences in the in vivo tRNA(Ala):tRNA(Ser) ratio in 159 and Pn16. Kinetic analysis revealed that MurM(159) acted during the lipid-linked stages of peptidoglycan synthesis, that the d-alanyl-d-alanine of the stem peptide and the lipid II N-acetylglucosaminyl group were not essential for substrate recognition, that epsilon-carboxylation of the lysine of the stem peptide was not tolerated, and that lipid II-alanine was a substrate, suggesting an evolutionary link to staphylococcal homologues of MurM such as FemA. Kinetic analysis also revealed that MurM recognized the acceptor stem and/or the TPsiC loop stem of the tRNA(Ala). It is anticipated that definition of the minimal structural features of MurM substrates will allow development of novel resistance inhibitors that will restore the efficacy of beta-lactams for treatment of pneumococcal infection. 相似文献
36.
Normal human hemopoietic cells such as early bone marrow progenitors, or lymphoma-derived cell lines such as Raji or JM cells, possess a low-affinity receptor specific for fibrinogen. This receptor triggers a mitogenic effect. It differs from the glycoprotein IIb-IIIa which is involved in fibrinogen-induced platelet aggregation. We demonstrate here that this mitogenic fibrinogen receptor (MFR) can be internalized or reexpressed, depending on culture conditions. Internalization was temperature-dependent. At 37 degrees C in the presence of cycloheximide or actinomycin D, the half-life of cell surface MFRs was 2 h, independent of receptor occupancy. Binding of fibrinogen to the MFR resulted in a down-regulation which was fibrinogen dose-dependent. This occurred in serum-supplemented medium but not in defined medium supplemented with fatty acids. Reexpression of MFRs could be induced in 28 to 42 h by serum removal. The down-regulation of mitogenic receptors in plasma or serum could explain why normal cells do not proliferate in the peripheral blood. 相似文献
37.
Molecular structure and interrelationships of multiresistance beta-lactamase transposons 总被引:6,自引:0,他引:6
Transposons coding for beta-lactamases OXA-3, OXA-4, OXA-5, LCR-1, and CARB-3 have been isolated and compared functionally and structurally with transposons for TEM-1, OXA-1, PSE-1, PSE-2, and PSE-4 enzymes. Each beta-lactamase gene type occurred in a unit together with resistance to other antibiotics, particularly streptomycin and sulfonamide but also chloramphenicol, mercuric ion, or gentamicin, kanamycin, and tobramycin. Restriction mapping, gene cloning, and DNA hybridization were used to compare the transposons and to localize their functional components. Although the multiresistance beta-lactamase transposons varied in size from 8 to 25 kb, the similarity of some of their restriction maps suggested a common derivation. Six of 12 transposons contained DNA segments homologous to the tnpR gene of transposon Tn21 and could complement a tnpR- Tn21 derivative. Consequently, these six transposons appear to have evolved from a common progenitor by acquisition of DNA coding for various beta-lactamases and other resistance genes. 相似文献
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40.
Extreme differences in rates of molecular evolution of foraminifera revealed by comparison of ribosomal DNA sequences and the fossil record 总被引:8,自引:3,他引:5
Pawlowski J; Bolivar I; Fahrni JF; de Vargas C; Gouy M; Zaninetti L 《Molecular biology and evolution》1997,14(5):498-505
Foraminifera have one of the best known fossil records among the
unicellular eukaryotes. However, the origin and phylogenetic relationships
of the extant foraminiferal lineages are poorly understood. To test the
current paleontological hypotheses on evolution of foraminifera, we
sequenced about 1,000 base pairs from the 3' end of the small subunit rRNA
gene (SSU rDNA) in 22 species representing all major taxonomic groups.
Phylogenies were derived using neighbor- joining, maximum-parsimony, and
maximum-likelihood methods. All analyses confirm the monophyletic origin of
foraminifera. Evolutionary relationships within foraminifera inferred from
rDNA sequences, however, depend on the method of tree building and on the
choice of analyzed sites. In particular, the position of planktonic
foraminifera shows important variations. We have shown that these changes
result from the extremely high rate of rDNA evolution in this group. By
comparing the number of substitutions with the divergence times inferred
from the fossil record, we have estimated that the rate of rDNA evolution
in planktonic foraminifera is 50 to 100 times faster than in some benthic
foraminifera. The use of the maximum-likelihood method and limitation of
analyzed sites to the most conserved parts of the SSU rRNA molecule render
molecular and paleontological data generally congruent.
相似文献