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51.
52.
Chaloin L Bigey P Loup C Marin M Galeotti N Piechaczyk M Heitz F Meunier B 《Bioconjugate chemistry》2001,12(5):691-700
The chemical nuclease metalloporphyrin (manganese(III) porphyrin) can cleave DNA irreversibly and can thus constitute a potential antitumor drug. However, these molecules show low permeability to cell surface membranes. We report here the conjugation of an amphipathic carrier peptide to improve considerably its cellular delivery. The metalloporphyrin-peptide conjugate can be internalized by cells within only 5 min of incubation with a yield as high as 80%. Furthermore, the metalloporphyrin-peptide conjugate is able to cleave in vitro high or low molecular weight DNA to the same extend as metalloporphyrin alone without affecting the sequence-specific cleaving activity of the porphyrin. The conjugate is 100-fold more efficient at inducing tumor cells death than the free metalloporphyrin via a mechanism involving genomic DNA cleavage. The results are promising for further therapeutic applications with antitumor drugs such as metalloporphyrin, and also with other existing drugs by using a carrier peptide system in order to improve the cellular uptake of such molecules. 相似文献
53.
54.
Sandell J Yu M Emond P Garreau L Chalon S Någren K Guilloteau D Halldin C 《Bioorganic & medicinal chemistry letters》2002,12(24):1195-3613
5-Methyl-6-nitroquipazine, a novel analogue of the potent and selective serotonin transporter inhibitor 6-nitroquipazine was synthesized and radiolabeled with tritium and the positron emitter carbon-11. [3H]5-methyl-6-nitroquipazine was found to have a Kd=51±7 pM. The high affinity and the facile labeling of [11C]5-methyl-6-nitroquipazine makes it a promising radioligand for visualization of the serotonin transporter with positron emission tomography. 相似文献
55.
A fluorescent labeling procedure, which does not perturb macromolecular conformations, was employed to bind a rhodamine derivative to the reducing end of several water-soluble polysaccharides by reductive amination in the presence of sodium cyanoborohydride. Fluorescence correlation spectroscopy, atomic force microscopy, and size exclusion chromatography were used to demonstrate that the conformations of the polysaccharides schizophyllan, polygalacturonic acid (PGUA), succinoglycan, and several dextrans were maintained following the labeling procedure. 相似文献
56.
A subset of chaperones and folding enzymes form multiprotein complexes in endoplasmic reticulum to bind nascent proteins 下载免费PDF全文
We demonstrate the existence of a large endoplasmic reticulum (ER)-localized multiprotein complex that is comprised of the molecular chaperones BiP; GRP94; CaBP1; protein disulfide isomerase (PDI); ERdj3, a recently identified ER Hsp40 cochaperone; cyclophilin B; ERp72; GRP170; UDP-glucosyltransferase; and SDF2-L1. This complex is associated with unassembled, incompletely folded immunoglobulin heavy chains. Except for ERdj3, and to a lesser extent PDI, this complex also forms in the absence of nascent protein synthesis and is found in a variety of cell types. Cross-linking studies reveal that the majority of these chaperones are included in the complex. Our data suggest that this subset of ER chaperones forms an ER network that can bind to unfolded protein substrates instead of existing as free pools that assembled onto substrate proteins. It is noticeable that most of the components of the calnexin/calreticulin system, which include some of the most abundant chaperones inside the ER, are either not detected in this complex or only very poorly represented. This study demonstrates an organization of ER chaperones and folding enzymes that has not been previously appreciated and suggests a spatial separation of the two chaperone systems that may account for the temporal interactions observed in other studies. 相似文献
57.
Eukaryotic cytochrome oxidases are composed of up to 13 subunits, of which three, subunits 1, 2 and 3, are mitochondrially encoded. In this study, yeast mutants were used to investigate the role of subunits 1 and 3 domains on the enzyme assembly. Mutation S203L in subunit 3 which abolished the respiratory growth, decreased cytochrome oxidase content, as measured by optical spectroscopy and immunodetection. Secondary mutations in subunits 1 and 3 restored (partly) the enzyme level. Two reversions reintroduced residues with a hydroxyl group at the primary mutation site (S203T) or in a subunit 3 transmembrane helix close to subunit 1 (G104S). These residues may be involved in hydrogen bonding which strengthen subunits 1-3 interaction. Two other reversions (A224V and Q137K) are located in P-side loops in subunit 1, which may be involved in the enzyme assembly. A mutation in residue A224 has been reported in a family presenting with encephalomyopathy. Surprisingly, the introduction of the 'human' mutation A224S and of a more drastic change A224F had no effect on the yeast enzyme. This might be explained by differences in local folding in the two enzymes. 相似文献
58.
Chikh GG Li WM Schutze-Redelmeier MP Meunier JC Bally MB 《Biochimica et biophysica acta》2002,1567(1-2):204-212
The therapeutic potential of selected peptides and proteins is enormous, with applications ranging from use as therapeutic vaccines, as modulators of intracellular signaling pathways and as highly selective agents capable of recognizing unique extracellular targets. We have been pursuing development of hybrid lipid-based carrier formulations designed to take advantage of the therapeutic benefits of peptides selected for their ability to act in a complementary fashion with the carrier system. In this regard, it is critical to have simple and versatile methods to promote and control the binding of diverse peptides to a broad range of carrier formulations. As demonstrated here, recombinant proteins and synthetic peptides containing poly-histidine residues (4 to 10) can be specifically bound to liposomes containing a metal-ion-chelating lipid, DOGS-NTA-Ni. The potential of this approach is demonstrated using two functional peptides, AntpHD-Cw3 (applications for vaccine production) and AHNP (specificity for Her-2 expressing cells). 相似文献
59.
Blanquet S Meunier JP Minekus M Marol-Bonnin S Alric M 《Applied and environmental microbiology》2003,69(5):2884-2892
The use of genetically engineered microorganisms such as bacteria or yeasts as live vehicles to carry out bioconversion directly in the digestive environment is an important challenge for the development of innovative biodrugs. A system that mimics the human gastrointestinal tract was combined with a computer simulation to evaluate the survival rate and cinnamate 4-hydroxylase activity of a recombinant model of Saccharomyces cerevisiae expressing the plant P450 73A1. The yeasts showed a high level of resistance to gastric and small intestinal secretions (survival rate after 4 h of digestion, 95.6% +/- 10.1% [n = 4]) but were more sensitive to the colonic conditions (survival rate after 4 h of incubation, 35.9% +/- 2.7% [n = 3]). For the first time, the ability of recombinant S. cerevisiae to carry out a bioconversion reaction has been demonstrated throughout the gastrointestinal tract. In the gastric-small intestinal system, 41.0% +/- 5.8% (n = 3) of the ingested trans-cinnamic acid was converted into p-coumaric acid after 4 h of digestion, as well as 8.9% +/- 1.6% (n = 3) in the stomach, 13.8% +/- 3.3% (n = 3) in the duodenum, 11.8% +/- 3.4% (n = 3) in the jejunum, and 6.5% +/- 1.0% (n = 3) in the ileum. In the large intestinal system, cinnamate 4-hydroxylase activity was detected but was too weak to be quantified. These results suggest that S. cerevisiae may afford a useful host for the development of biodrugs and may provide an innovative system for the prevention or treatment of diseases that escape classical drug action. In particular, yeasts may provide a suitable vector for biodetoxication in the digestive environment. 相似文献
60.
Bossard C Laurell H Van den Berghe L Meunier S Zanibellato C Prats H 《Nature cell biology》2003,5(5):433-439
Basic fibroblast growth factor (bFGF or FGF-2) exerts its pleiotropic activities both as an exogenous and an intracellular factor. FGF-1 and FGF-2 are prototypes for this dual signalling, but the mechanisms of their intracellular actions remain unknown. Here we show that Translokin, a cytoplasmic protein of relative molecular mass 55,000 (M(r) 55K), interacts specifically with the 18K form of FGF-2. Translokin is ubiquitously expressed and colocalizes with the microtubular network. As Translokin does not interact with FGF-1, we used a strategy based on FGF-1-FGF-2 chimaeras to map the interacting regions in FGF-2 and to generate Nb1a2, a non-interacting variant of FGF-2. Although most of the FGF-2 properties are preserved in Nb1a2, this variant is defective in intracellular translocation and in stimulating proliferation. The fusion of a nuclear localization signal to Nb1a2 restores its mitogenic activity and its nuclear association. Inhibiting Translokin expression by RNA interference reduces the translocation of FGF-2 without affecting the intracellular trafficking of FGF-1. Our data show that the nuclear association of internalized FGF-2 is essential for its mitogenic activity and that Translokin is important in this translocation pathway. 相似文献