We have tested the hypothesis that oxidation of lung surfactant results in loss ofsurface tension lowering function. Porcine lung surfactant was exposed to conditions known to cause lipid peroxidation (0.2 mM FeCl2 + 0.1 mM H202 or 5 ,uM CuC12). Lipid peroxidation was verified by detection of conjugated dienes, thiobarbituric acid reactive substances, fluorescent products, hydroxy alkenals, and loss of unsaturated fatty acids. Exposed samples had significantly diminished surface tension lowering ability in vitro as measured in a bubble surfactometer. Samples exposed to FeCl2 + H202 had significantly diminished surface tension lowering ability in vivo as indicated by their reduced ability to improve lung compliance of surfactant-deficient fetal rabbits. Oxidation of phospholipid mixtures with surface tension lowering activity and containing unsaturated acyl groups resulted in partial loss of activity as determined in vitro. These results suggest that the effect of oxidants on lung surfactant function is due, in part, to effects on the phospholipid components and that acute pulmonary inflammation accompanied by oxygen radical production may result in surfactant lipid peroxidation and loss of surface tension lowering function. (J. Clin. Invest. 1994. 93:2608-2615
The IL-17 cytokine family is associated with multiple immune and autoimmune diseases and comprises important diagnostic and therapeutic targets. This work reports the development of epitope-targeted ligands designed for differential detection of human IL-17F and its closest homologue IL-17A. Non-overlapping and unique epitopes on IL-17F and IL-17A were identified by comparative sequence analysis of the two proteins. Synthetic variants of these epitopes were utilized as targets for in situ click screens against a comprehensive library of synthetic peptide macrocycles with 5-mer variable regions. Single generation screens yielded selective binders for IL-17F and IL-17A with low cross-reactivity. Macrocyclic peptide binders against two distinct IL-17F epitopes were coupled using variable length chemical linkers to explore the physical chemistry of cooperative binding. The optimized linker length yielded a picomolar affinity binder, while retaining high selectivity. The presented method provides a rational approach towards targeting discontinuous epitopes, similar to what is naturally achieved by many B cell receptors.
Chemically synthesized, small peptides that bind with high affinity and specificity to CD8-expressing (CD8+) tumorinfiltrating T cells, yet retain the desirable characteristics of small molecules, hold valuable potential for diagnostic molecular imaging of immune response. Here, we report the development of 18 F-labeled peptides targeting human CD8α with nanomolar affinity via the strain-promoted sydnone−alkyne cycloaddition with 4-[ 18 F]fluorophenyl sydnone. The 18 F-sydnone is produced in one step, in high radiochemical yield, and the peptide labeling proceeds rapidly. A hydrophilic chemical linker results in a tracer with favorable pharmacokinetic properties and improved image contrast, as demonstrated by in vivo PET imaging studies.
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