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  • 1
    Publication Date: 2013-02-23
    Description: Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jin-Hyo -- Resende, Ricardo -- Wennekes, Tom -- Chen, Hong-Ming -- Bance, Nicole -- Buchini, Sabrina -- Watts, Andrew G -- Pilling, Pat -- Streltsov, Victor A -- Petric, Martin -- Liggins, Richard -- Barrett, Susan -- McKimm-Breschkin, Jennifer L -- Niikura, Masahiro -- Withers, Stephen G -- G0600514/Medical Research Council/United Kingdom -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2013 Apr 5;340(6128):71-5. doi: 10.1126/science.1232552. Epub 2013 Feb 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23429702" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antiviral Agents/*chemistry/pharmacology ; Crystallography, X-Ray ; Dogs ; Enzyme Inhibitors/*chemistry/pharmacology ; Humans ; Madin Darby Canine Kidney Cells ; Neuraminidase/*antagonists & inhibitors/chemistry ; Orthomyxoviridae/*drug effects/enzymology ; Oseltamivir/chemistry/pharmacology ; Protein Conformation ; Sialic Acids/*chemistry/pharmacology ; Structure-Activity Relationship ; Zanamivir/chemistry/pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    ISSN: 1432-8798
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The nucleoprotein (NP) gene from influenza virus A/Shearwater/Australia/72 has been expressed intracellularly in bothE. coli and insect cells.E. coli-derived NP was identified by Western blot analysis as a 56 kDa protein which co-migrates with virion-derived NP. This protein was purified by immunoaffinity chromatography and a nitrocellulose binding assay showed that NP formed complexes with positive- and negative-sense influenza neuraminidase RNA transcribed in vitro. ELISA and Western blot analysis revealed that recombinant NP of 56 kDa was produced in high yields in insect cells using a baculovirus vector. Immunofluorescence microscopy revealed that NP was localised to the nucleus of infected insect cells.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Cells of an antigen-specific T-cell clone, A37.4, were treated with the proteolytic enzymes trypsin or pronase to remove the T-cell antigen receptor. Removal of the receptor, analysed by surface labelling and non-reduced/reduced gel electrophoresis, stimulated the cells to synthesize new protein rapidly. New membrane protein was readily detectable within 3 h after reculture, and it was able to interact with antigen-presenting cells, since the T cells could be stimulated to produce interferon. Treatment of cells with metabolic inhibitors demonstrated that there was only a small cytoplasmic pool of protein, and de novo synthesis of mRNA was necessary for quantitative replacement of the membrane protein. The protein also required glycosylation for transport and insertion into the membrane. Despite rapid resynthesis of new receptor, when surface-labelled cells were recultured either with or without antigen-presenting cells, there was not a rapid turnover of the receptor. There was also no evidence of any loss of receptor from the membrane of antigen-stimulated cells or of any shedding of receptor into the culture medium.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1365-3083
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Antibodies produced in the primary response to the hupten 2-phenyl oxazolone (OX) express a eruss-reactive idiotype in BALB/c and DBA/2 mice. We studied the response in hyperimmunized mice, using ascites produced after multiple immunizations with an OX conjugate and by generating monoclonal antibodies. A competitive radioimmunoassay was developed using a rabbit :tnti-idiotype antiserum raised against purified hyperimmune anti-OX antibodies, Mice from strains including CBA. C3H/He and B10.BR expressed all the deteminants found in BALB/c serum, although at a lower titre. C57BL/6 mice, however, only expressed some of the BALB/c determinants. We isolated a monoclonal antibody, 1F9, which expressed some of the determinants found in BALB'e serum. All the cross-reactive idiotopes expressed on 1F9 were also expressed in the above strains including C57BL/6. Almost every BALB/c anti-OX antibody also expressed the 1F9 determinants. There are thus determinants of the BALB/c OX idiotype which arc expressed in a number of different strains previously thought to be negative for the idiotype.
    Type of Medium: Electronic Resource
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