Biomedical subjects
E L Becker
Publications and source records attributed to E L Becker.
Comments on antigenic analyses.
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Acute transient hearing loss after ethacrynic acid therapy.
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The development of permeability activity by undiluted plasma on exposure to glass.
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Apparent volumes of distribution of water, electrolytes and hemoglobin within the lung.
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Synthetic formyl-methionyl chemoattractants: a conformation-activity study of oxidized tripeptides.
The two diastereomeric sulphoxides and the sulphone derived from the formyl-methionyl tripeptide chemoattractant CHO-L-Met-L-Phe-OMe have been synthesized and fully characterized. The diastereomeric sulphoxide tripeptides have been separated at the stage of their N-tert-butyloxycarbonyl synthetic precursors. All of the oxidized sulphur derivatives induce secretion of granule enzymes with ED50s from 1-2 x 10(-9) M with no significant differences in activity among them. They are also active to the same relative extent in inducing chemotaxis. In parallel, a solution conformational analysis has been performed in solvents of widely different polarities and capabilities of H-bond formation using circular dichroism, infrared absorption and 1H nuclear magnetic resonance. No significant propensity for formation of intramolecularly (C = O...H-N) H-bonded folded forms has been detected in any of the four tripeptides. Intermolecular S = O...H-N interactions are postulated to tentatively explain the 1H nuclear magnetic resonance behavior of the Met and, particularly, Leu NH resonances of the two sulphoxide tripeptides in CDCl3 solution. The biological and conformational data agree with the recently proposed model of the chemotactic peptide receptor of rabbit neurotrophils, which involves the extended backbone of the integrity of the Met side-chain sulphide sulphur atom as a corollary point of ligand interaction.
Lipopolysaccharide in combination with serum potentiates the stimulated activity of phospholipase D in human neutrophils via CD14.
The addition of fMet-Leu-Phe or phorbol 12-myristate 13-acetate to human neutrophils stimulates phospholipase D activity as evidenced by the release of phosphatidic acid and the generation of diacylglycerol, and in the presence of ethanol the formation of phosphatidyl ethanol. The activation of phospholipase D by either the chemotactic factor or active phorbol ester is inhibited by the tyrosine kinase inhibitor erbstatin. The fMet-Leu-Phe-induced stimulation of this enzyme is greatly potentiated in cells which have been preincubated with low concentrations of lipopolysaccharide and serum. The presence of serum is essential for the potentiation by low concentrations of lipopolysaccharide. Moreover, the monoclonal antibody MY4(IgG2b) against CD14 inhibits the potentiation by the low concentration of lipopolysaccharide. These data suggest three important points. First, a tyrosine kinase step is necessary for the activation of phospholipase D. This suggests that the phospholipase D enzyme needs to be phosphorylated on tyrosine residues to be activated. Second, low concentrations of lipopolysaccharide, in the presence of serum, can potentiate the stimulated activity of this enzyme. Third, the priming action of the lipopolysaccharide-serum complex is mediated by CD14.
A conformation-activity study of the [L-(alpha Me)Phe]3 analog of the formyl methionyl tripeptide chemoattractant.
CHO-L-Met-L-Leu-L-(alpha Me)Phe-OMe, an analog of the formyl methionyl tripeptide chemoattractant CHO-L-Met-L-Leu-L-Phe-OH, was synthesized by solution methods and fully characterized. This compound was prepared to determine the effect of the incorporation of a conformationally restricted C alpha,alpha-disubstituted alpha-amino acid residue at position 3 on the relation of three-dimensional structure to biological activity. The peptide was tested for its ability to induce granule enzyme secretion from rabbit peritoneal polymorphonuclear leukocytes. In parallel, a conformational analysis was performed in the crystal state by x-ray diffraction and in organic solution by infrared absorption and 1H nuclear magnetic resonance. These biological and conformational data are discussed in relation to those of the prototype tripeptide and its methyl ester.
Conformationally restricted formyl methionyl tripeptide chemoattractants: a three-dimensional structure-activity study of analogs incorporating a C alpha,alpha-dialkylated glycine at position 2.
The conformationally restricted CHO-L-Met-Xxx-L-Phe-OY (where Xxx = Aib, Ac3c, Ac5c, Ac6c, and Ac7c; Y = H, Me) tripeptides, analogs of the chemoattractant CHO-L-Met-L-Leu-L-Phe-OH, have been synthesized in solution by classical methods and fully characterized. Compounds were compared to determine the combined effect of backbone conformational preferences and side-chain bulkiness on the relation of three-dimensional structure to biological activity. Each peptide was tested for its ability to induce granule enzyme secretion from rabbit peritoneal polymorphonuclear leukocytes. In parallel, a conformational analysis on the CHO-blocked peptide and their tertbutyloxycarbonylated synthetic precursors was performed in the crystal state and in solution using X-ray diffraction, infrared absorption, and 1H nuclear magnetic resonance. The biological and conformational data are discussed in relation to the proposed model of the chemotactic peptide receptor of rabbit neutrophils.
Enzymatic mechanisms in complement-dependent chemotaxis.
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Enzymatic mechanisms in the chemotaxis of neutrophils.
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Masugi nephritis: the renal lesion and the coagulation processes.
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Cellular mechanisms and involvement in acute allergic reactions. Introduction.
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Conformationally constrained formyl methionyl tripeptides: structure-function study of analogs containing alpha,beta-dehydrophenylalanine and dehydroleucine.
In order to probe the role of peptide backbone conformation on the biological activity of chemotactic peptides through conformationally constrained peptides, we synthesized the following three analogs of N-formyl-Met-Leu-Phe-OH (fMLF) containing dehydrophenylalanine (delta ZPhe) and dehydroleucine (delta ZLeu): formyl-Met-delta ZPhe-Phe-OCH3 (1), formyl-Met-delta ZLeu-Phe-OCH3 (2) and formyl-Met-delta ZPhe-delta ZPhe-OCH3 (3) and studied their conformational behavior in solution by 1H NMR and IR spectroscopy. The conformation of (1) was also examined by x-ray diffraction methods. Biological activity of these analogs was assessed for their ability to induce the release of beta-glucosaminidase from rabbit neutrophils. In addition, the chemotactic activity of analog (2) was also determined. We found that, in the solid state, (1) favors a type II beta-turn structure, stabilized by a 4-->1 intramolecular hydrogen bond. A similar structure was reported recently for (2) also. 1H NMR studies in solution suggest that the Phe NH is solvent shielded in both (1) and (2) and that a major population of peptide molecule exists in an intramolecular hydrogen bond stabilized type II beta-turn conformation. None of the NH groups in (3) and another analog, formyl-Met-Phe-Phe-OCH3 (4), appear solvent shielded, favoring an extended structure for these analogs. Analogs (2) and (4) are highly active indicating that both extended and beta-turn backbone conformations may be compatible with high activity and that the phenylalanine ring in the middle position is well accepted. Highly reduced activities of (1) and (3) suggest that delta ZPhe residue in position 2, irrespective of the preferred peptide backbone conformation, is not acceptable for high bioactivity. These results suggest that an induced fit mechanism may possibly be the most relevant one, but the nature and the topography of the side chains, particularly the middle residue, may be crucial for appropriate receptor ligand interactions.