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排序方式: 共有158条查询结果,搜索用时 31 毫秒
81.
Stanley D. Chamberlain Anikó M. Redman Samarjit Patnaik Keith Brickhouse Yen-Chiat Chew Felix Deanda Roseanne Gerding Huangshu Lei Ganesh Moorthy Mark Patrick Kirk L. Stevens Joseph W. Wilson J. Brad Shotwell 《Bioorganic & medicinal chemistry letters》2009,19(2):373-377
Initial evaluation of a series 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidines revealed a C(1′) carboxamide was preferred for sub-micromolar in vitro potency against IGF-1R. Subsequent solution stability studies with 1 revealed a susceptibility toward acid-induced intramolecular cyclization with the C(1′) carboxamide. Herein, we describe several successful approaches toward generating both potent and acid-stable inhibitors of IGF-1R within the 4,6-bis-anilino-1H-pyrrolo[2,3-d]pyrimidine template. 相似文献
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83.
Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans 总被引:23,自引:0,他引:23
McConkey SJ Reece WH Moorthy VS Webster D Dunachie S Butcher G Vuola JM Blanchard TJ Gothard P Watkins K Hannan CM Everaere S Brown K Kester KE Cummings J Williams J Heppner DG Pathan A Flanagan K Arulanantham N Roberts MT Roy M Smith GL Schneider J Peto T Sinden RE Gilbert SC Hill AV 《Nature medicine》2003,9(6):729-735
In animals, effective immune responses against malignancies and against several infectious pathogens, including malaria, are mediated by T cells. Here we show that a heterologous prime-boost vaccination regime of DNA either intramuscularly or epidermally, followed by intradermal recombinant modified vaccinia virus Ankara (MVA), induces high frequencies of interferon (IFN)-gamma-secreting, antigen-specific T-cell responses in humans to a pre-erythrocytic malaria antigen, thrombospondin-related adhesion protein (TRAP). These responses are five- to tenfold higher than the T-cell responses induced by the DNA vaccine or recombinant MVA vaccine alone, and produce partial protection manifest as delayed parasitemia after sporozoite challenge with a different strain of Plasmodium falciparum. Such heterologous prime-boost immunization approaches may provide a basis for preventative and therapeutic vaccination in humans. 相似文献
84.
We describe here the X-ray crystal structure of NF-kappaB p50/RelB heterodimer bound to a kappaB DNA. Although the global modes of subunit association and kappaB DNA recognition are similar to other NF-kappaB/DNA complexes, this complex reveals distinctive features not observed for non-RelB complexes. For example, Lys274 of RelB is removed from the protein-DNA interface whereas the corresponding residues in all other subunits make base-specific contacts. This mode of binding suggests that RelB may allow the recognition of more diverse kappaB sequences. Complementary surfaces on RelB and p50, as revealed by the crystal contacts, are highly suggestive of assembly of multiple p50/RelB heterodimers on tandem kappaB sites in solution. Consistent with this model our in vitro binding experiments reveal optimal assembly of two wild-type p50/RelB heterodimers on tandem HIV kappaB DNA with 2 bp spacing but not by a mutant heterodimer where one of the RelB packing surface is altered. We suggest that multiple NF-kappaB dimers assemble at diverse kappaB promoters through direct interactions utilizing unique protein-protein interaction surfaces. 相似文献
85.
An alternatively spliced cytochrome P4501A1 in human brain fails to bioactivate polycyclic aromatic hydrocarbons to DNA-reactive metabolites 总被引:1,自引:0,他引:1
Kommaddi RP Turman CM Moorthy B Wang L Strobel HW Ravindranath V 《Journal of neurochemistry》2007,102(3):867-877
CYP1A1, a cytochrome P450 enzyme, metabolizes polycyclic aromatic hydrocarbons to genotoxic metabolite(s) that bind to DNA and initiate carcinogenesis. RT-PCR amplification of the complete open reading frame of CYP1A1 generated an amplicon of 1593 bp having deletion of 87 bp of exon-6 that translated into functional P450 enzyme. Unlike wild type CYP1A1, exon 6 del CYP1A1 did not metabolize polycyclic aromatic hydrocarbons such as, benzo(a)pyrene to genotoxic, ultimate carcinogens that form DNA adducts. Exon 6 del CYP1A1 metabolized ethoxyresorufin (the classical substrate for CYP1A1) less efficiently compared with wild type CYP1A1 while pentoxy and benzyloxyresorufin (classical substrates for CYP2B) were dealkylated more efficiently. In silico docking showed alteration of the substrate access channel in exon 6 del CYP1A1 such that benzo(a)pyrene does not bind in any orientation that would permit the formation of carcinogenic metabolites. Genotyping revealed that the splice variant was not generated due to differences in genomic DNA sequence and the variant was present only in brain but not in liver, kidney, lung, or heart from the same individual. We provide evidence that unique P450 enzymes, generated by alternate splicing in a histiospecific manner can modify genotoxic potential of carcinogens such as benzo(a)pyrene by altering their biotransformation pathway. 相似文献
86.
Sudeep Kumar Aditya Kapoor Nagaraja Moorthy Yash Lokhandwala 《Indian pacing and electrophysiology journal》2015,15(1):76-78
Lead induced transient right bundle branch block is not uncommon during pacemaker implantation. We describe a patient with old anterior wall myocardial infarction with severe left ventricular dysfunction presenting with recurrent ventricular tachycardia who developed transient right bundle branch block and pseudomyocardial infacrction pattern during AICD implantation.Key words: Pseudo Myocardial Infarction, AICD implantation 相似文献
87.
Balakrishnan?S. Moorthy Hamed?Tabatabaei Ghomi Markus?A. Lill Elizabeth?M. Topp 《Biophysical journal》2015,108(4):937-948
A mechanistic understanding of the intermolecular interactions and structural changes during fibrillation is crucial for the design of safe and efficacious glucagon formulations. Amide hydrogen/deuterium exchange with mass spectrometric analysis was used to identify the interactions and amino acids involved in the initial stages of glucagon fibril formation at acidic pH. Kinetic measurements from intrinsic and thioflavin T fluorescence showed sigmoidal behavior. Secondary structural measurement of fibrillating glucagon using far-UV circular dichroism spectroscopy showed changes in structure from random coil → α-helix → β-sheet, with increase in α-helix content during the lag phase followed by increase in β-sheet content during the growth phase. Hydrogen/deuterium exchange with mass spectrometric analysis of fibrillating glucagon suggested that C-terminal residues 22–29 are involved in interactions during the lag phase, during which N-terminal residues 1–6 showed no changes. Molecular dynamics simulations of glucagon fragments showed C-terminal to C-terminal interactions with greater α-helix content for the 20–29 fragment, with hydrophobic and aromatic residues (Phe-22, Trp-25, Val-23, and Met-27) predominantly involved. Overall, the study shows that glucagon interactions during the early phase of fibrillation are mediated through C-terminal residues, which facilitate the formation of α-helix-rich oligomers, which further undergo structural rearrangement and elongation to form β-sheet-rich mature fibrils. 相似文献
88.
89.
Palanki MS Bhat A Lappe RW Liu B Oates B Rizzo J Stankovic N Bradshaw C 《Bioorganic & medicinal chemistry letters》2012,22(13):4249-4253
We have developed modified maleimide novel linkers with improved chemical stability that could potentially be used in conjugating various pharmacophores such as oligo nucleotides, peptides, and proteins to antibodies to afford novel biologics with well-defined therapeutic benefits and improved pharmacokinetic properties. These linkers expand the array of tools available for bioconjugation of pharmacophores to antibodies. 相似文献
90.