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排序方式: 共有181条查询结果,搜索用时 15 毫秒
81.
Ian M. Bell Rodney A. Bednar Halea A. Corcoran John F. Fay Steven N. Gallicchio Victor K. Johnston James C. Hershey Cynthia M. Miller-Stein Eric L. Moore Scott D. Mosser Shane A. Roller Christopher A. Salvatore Cory R. Theberge Bradley K. Wong C. Blair Zartman Stefanie A. Kane Theresa M. Williams Samuel L. Graham Joseph P. Vacca 《Bioorganic & medicinal chemistry letters》2009,19(16):4740-4742
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species. 相似文献
82.
Jennifer Carpenter Stephan Hutter John F. Baines Julia Roller Sarah S. Saminadin-Peter John Parsch Francis M. Jiggins 《PloS one》2009,4(8)
Background
Bacterial and fungal infections induce a potent immune response in Drosophila melanogaster, but it is unclear whether viral infections induce an antiviral immune response. Using microarrays, we examined the changes in gene expression in Drosophila that occur in response to infection with the sigma virus, a negative-stranded RNA virus (Rhabdoviridae) that occurs in wild populations of D. melanogaster.Principal Findings
We detected many changes in gene expression in infected flies, but found no evidence for the activation of the Toll, IMD or Jak-STAT pathways, which control immune responses against bacteria and fungi. We identified a number of functional categories of genes, including serine proteases, ribosomal proteins and chorion proteins that were overrepresented among the differentially expressed genes. We also found that the sigma virus alters the expression of many more genes in males than in females.Conclusions
These data suggest that either Drosophila do not mount an immune response against the sigma virus, or that the immune response is not controlled by known immune pathways. If the latter is true, the genes that we identified as differentially expressed after infection are promising candidates for controlling the host''s response to the sigma virus. 相似文献83.
84.
Krajewski K Long YQ Marchand C Pommier Y Roller PP 《Bioorganic & medicinal chemistry letters》2003,13(19):3203-3205
Dimers of known HIV-1 integrase inhibitory hexapeptide H-His-Cys-Lys-Phe-Trp-Trp-NH(2) containing different lengths of cross linkers in the place of cysteine residue, were designed, and synthesized. The inhibitory potency of these dimeric peptides is consistently higher than the lead hexapeptide. The dimeric peptide with djenkolic acid linker exhibited IC(50) values of 5.3 and 6.5 microM, for 3'-end processing and strand transfer, respectively. 相似文献
85.
Li P Zhang M Long YQ Peach ML Liu H Yang D Nicklaus M Roller PP 《Bioorganic & medicinal chemistry letters》2003,13(13):2173-2177
Development of Grb2-SH2 domain antagonists is an effective approach to inhibit the growth of malignant cells by modulating Grb2-related Ras signaling. We report here potent Grb2-SH2 domain antagonists that do not rely on phosphotyrosine or its mimics. These non-phosphorylated antagonists were developed and further modified by constraining the backbone conformation and optimizing amino acid side chains of a phage library-derived peptide, G1TE. After extensive SAR studies and structural optimization, non-phosphorylated peptide 12 was discovered with an IC(50) of 75 nM. This potent peptidomimetic provides a novel template for the development of non-pTyr containing Grb2-SH2 domain antagonists and acts as a chemotherapeutic lead for the treatment of erbB2-related cancer. 相似文献
86.
Ultrastructural localization of the herpes simplex virus type 1 UL31, UL34, and US3 proteins suggests specific roles in primary envelopment and egress of nucleocapsids
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The wild-type UL31, UL34, and US3 proteins localized on nuclear membranes and perinuclear virions; the US3 protein was also on cytoplasmic membranes and extranuclear virions. The UL31 and UL34 proteins were not detected in extracellular virions. US3 deletion caused (i) virion accumulation in nuclear membrane invaginations, (ii) delayed virus production onset, and (iii) reduced peak virus titers. These data support the herpes simplex virus type 1 deenvelopment-reenvelopment model of virion egress and suggest that the US3 protein plays an important, but nonessential, role in the egress pathway. 相似文献
87.
Effects of charged cluster mutations on the function of herpes simplex virus type 1 UL34 protein 总被引:2,自引:0,他引:2
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Bjerke SL Cowan JM Kerr JK Reynolds AE Baines JD Roller RJ 《Journal of virology》2003,77(13):7601-7610
Herpes simplex virus type 1 (HSV-1) is a DNA virus that acquires an envelope by budding into the inner nuclear membrane of an infected cell. Recombinant HSV-1 lacking the U(L)34 gene cannot undergo this event. U(L)34 and U(L)31, another viral protein, colocalize in an infected cell and are necessary and sufficient to target both proteins to the inner nuclear envelope. In order to define and characterize sequences of U(L)34 that are necessary for primary envelopment to occur, a library of 19 U(L)34 charged cluster mutants and a truncation mutant lacking the putative transmembrane domain (DeltaTM) were generated. Mutants in this library were analyzed in a complementation assay for their ability to function in the production of infectious virus. Seven of the mutants failed to complement a U(L)34-null virus. The remainder of the mutants complemented at or near wild-type U(L)34 levels. Failure of a mutant protein to function might be the result of incorrect subcellular localization. To address this possibility, confocal microscopy was used to determine the localization of the U(L)34 protein in charged cluster mutants and DeltaTM. In transfection-infection experiments, all of the functional U(L)34 mutants and four of the six noncomplementing mutants localized to the inner nuclear envelope in a manner indistinguishable from that of wild-type U(L)34. All of the noncomplementing U(L)34 mutants mediated proper localization of U(L)31. Charged clusters critical for U(L)34 function are dispersed throughout the protein sequence and do not correlate well with highly conserved regions of the protein. These data suggest that U(L)34 has at least one function in addition to mediating proper localization of U(L)31 in infected cells and provide further support for the role of U(L)34 in mediating proper localization of U(L)31 in infected cells. 相似文献
88.
Stability and peptide binding specificity of Btk SH2 domain: molecular basis for X-linked agammaglobulinemia
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Tzeng SR Pai MT Lung FD Wu CW Roller PP Lei B Wei CJ Tu SC Chen SH Soong WJ Cheng JW 《Protein science : a publication of the Protein Society》2000,9(12):2377-2385
X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton's tyrosine kinase (Btk). The absence of functional Btk leads to failure of B-cell development that incapacitates antibody production in XLA patients leading to recurrent bacterial infections. Btk SH2 domain is essential for phospholipase C-gamma phosphorylation, and mutations in this domain were shown to cause XLA. Recently, the B-cell linker protein (BLNK) was found to interact with the SH2 domain of Btk, and this association is required for the activation of phospholipase C-gamma. However, the molecular basis for the interaction between the Btk SH2 domain and BLNK and the cause of XLA remain unclear. To understand the role of Btk in B-cell development, we have determined the stability and peptide binding affinity of the Btk SH2 domain. Our results indicate that both the structure and stability of Btk SH2 domain closely resemble with other SH2 domains, and it binds with phosphopeptides in the order pYEEI > pYDEP > pYMEM > pYLDL > pYIIP. We expressed the R288Q, R288W, L295P, R307G, R307T, Y334S, Y361C, L369F, and 1370M mutants of the Btk SH2 domain identified from XLA patients and measured their binding affinity with the phosphopeptides. Our studies revealed that mutation of R288 and R307 located in the phosphotyrosine binding site resulted in a more than 200-fold decrease in the peptide binding compared to L295, Y334, Y361, L369, and 1370 mutations in the pY + 3 hydrophobic binding pocket (approximately 3- to 17-folds). Furthermore, mutation of the Tyr residue at the betaD5 position reverses the binding order of Btk SH2 domain to pYIIP > pYLDL > pYDEP > pYMEM > pYEEI. This altered binding behavior of mutant Btk SH2 domain likely leads to XLA. 相似文献
89.
Antimicrobial actions of degraded and native chitosan against spoilage organisms in laboratory media and foods 总被引:19,自引:0,他引:19
The objective of this study was to determine whether chitosan (poly-beta-1,4-glucosamine) and hydrolysates of chitosan can be used as novel preservatives in foods. Chitosan was hydrolyzed by using oxidative-reductive degradation, crude papaya latex, and lysozyme. Mild hydrolysis of chitosan resulted in improved microbial inactivation in saline and greater inhibition of growth of several spoilage yeasts in laboratory media, but highly degraded products of chitosan exhibited no antimicrobial activity. In pasteurized apple-elderflower juice stored at 7 degrees C, addition of 0.3 g of chitosan per liter eliminated yeasts entirely for the duration of the experiment (13 days), while the total counts and the lactic acid bacterial counts increased at a slower rate than they increased in the control. Addition of 0.3 or 1.0 g of chitosan per kg had no effect on the microbial flora of hummus, a chickpea dip; in the presence of 5.0 g of chitosan per kg, bacterial growth but not yeast growth was substantially reduced compared with growth in control dip stored at 7 degrees C for 6 days. Improved antimicrobial potency of chitosan hydrolysates like that observed in the saline and laboratory medium experiments was not observed in juice and dip experiments. We concluded that native chitosan has potential for use as a preservative in certain types of food but that the increase in antimicrobial activity that occurs following partial hydrolysis is too small to justify the extra processing involved. 相似文献
90.
Effects of horsefly (Tabanidae) salivary gland extracts on isolated perfused rat heart 总被引:1,自引:0,他引:1
Rajská P Knezl V Kazimírová M Takác P Roller L Vidlicka L Ciampor F Labuda M Weston-Davies W Nuttall PA 《Medical and veterinary entomology》2007,21(4):384-389
The speed with which horseflies (Diptera: Tabanidae) obtain a bloodmeal suggests they have potent vasodilators. We used isolated perfused rat heart to examine the vasoactivity of salivary gland extracts (SGEs) of three horsefly species, Hybomitra bimaculata Macquart, Tabanus bromius Linnaeus and Tabanus glaucopis Meigen. Administration of horsefly SGEs to the heart produced biphasic coronary responses: a decrease and subsequent increase in coronary flow (CF), characterized by initial vasoconstriction followed by prolonged vasodilation of coronary vessels. However, although SGEs of H. bimaculata induced a significant decrease in left ventricular pressure (LVP), the effect on changes in CF was not significant except at the highest dose tested. The ability to reduce LVP without significantly lowering CF, or affecting heart rate and rhythm, represents a unique set of properties that have considerable therapeutic potential if they can be reproduced by a single molecule. 相似文献