Peptides as ligands for immunoadsorption exhibit several potential advantages over native proteins. Two newly developed adsorbers are based on peptides covalently coupled to sepharose CL-4B. Globaffin is capable of binding immunoglobulins independent from their antigen specificity and thus, applicable in transplant recipients and several antibody mediated autoimmune diseases. Among others, the most important disorders suitable for the treatment with Globaffin are rheumatoid arthritis, systemic lupus erythematosus, and acute renal transplant rejection. Coraffin is a specific adsorber using two linear peptide ligands mimicking epitopes of the beta1-adrenergic receptor, that bind corresponding autoantibodies from patients suffering from idiopathic dilated cardiomyopathy. Specific immunoadsorption has been shown to be beneficial for patients with dilated cardiomyopathy. Coraffin can be used as a new therapeutic option for these patients, who get only limited benefit from medical therapy. Both adsorbers may be combined with all approved apheresis control devices available.
A technique for systematic peptide variation by a combination of rational and evolutionary approaches is presented. The design scheme consists of five consecutive steps: (i) identification of a ''seed peptide'' with a desired activity, (ii) generation of variants selected from a physicochemical space around the seed peptide, (iii) synthesis and testing of this biased library, (iv) modeling of a quantitative sequence-activity relationship by an artificial neural network, and (v) de novo design by a computer-based evolutionary search in sequence space using the trained neural network as the fitness function. This strategy was successfully applied to the identification of novel peptides that fully prevent the positive chronotropic effect of anti- 1 -adrenoreceptor autoantibodies from the serum of patients with dilated cardiomyopathy. The seed peptide, comprising 10 residues, was derived by epitope mapping from an extracellular loop of human  1 -adrenoreceptor. A set of 90 peptides was synthesized and tested to provide training data for neural network development. De novo design revealed peptides with desired activities that do not match the seed peptide sequence. These results demonstrate that computer-based evolutionary searches can generate novel peptides with substantial biological activity.Molecular design aims to identify compounds with a desired activity and to rationally modify molecular structures to yield desired or improved molecular properties. Two principal problems need to be solved: first, a search strategy must be developed for exploiting the potentially huge number of compounds; second, for any rational design approach a model must be available to guide the systematic modification of molecular structures. Rational molecular design can be successful only with profound knowledge of the inf luence of structural modifications on molecular function. An alternative approach is to use evolutionary strategies in which optimization of molecular properties is achieved by a cyclic variation-selection process; no detailed understanding of the respective structure-activity relationship is required. This process can be performed in vivo, in vitro, or even entirely by computer (''in machina '' or ''in silico''). Usually, a large number of compounds must be synthesized and tested per evolutionary cycle to avoid trapping into premature convergence, and the optimization process bears the danger of being merely superior to pure random search. If, however, this limitation can be overcome, e.g., by massively parallel screening and smart variation of molecular structures, evolutionary design can be a powerful method for rapid identification of potential lead compounds.We have developed a design approach combining the advantages of a computer-based evolutionary search with a knowledge-based rational access to reduce the time and effort needed to obtain desirable molecules. The goal is to minimize the number of bench experiments by making extensive use of the information provided by the results of each in vitro o...
Pemphigoid gestationis (PG) is a subepidermal autoimmune blistering disease characterized by self-reactive T and B cells specific for the transmembrane hemidesmosomal protein type XVII collagen/BP180. Major T and B cell epitopes are located within the immunodominant 16 th non-collagenous domain A (NC16A) of type XVII collagen. The aim of the present study was to map the pathogenically relevant epitopes targeted by blister-inducing patients' autoantibodies. For this purpose, we used an in vitro model of autoantibody-induced leukocyte-dependent dermal-epidermal separation. Pre-adsorption against a recombinant form of the NC16A region abolished the blister-inducing potential of autoantibodies from all PG patients. Using overlapping synthetic peptides, we demonstrated that PG autoantibodies bind to two defined epitopes within the NC16A region (aa 500-514 and aa 511-523). Importantly, preadsorption using an affinity matrix containing these epitopes completely abolished dermal-epidermal separation induced by PG autoantibodies. This study identifies the epitopes relevant for blister induction in PG and should facilitate the development of an antigen-specific immunoadsorption therapy for this disease.
were used to identify immunologically reactive regions of flagellin. Five serum specimens from patients with late manifestations of Lyme disease and borrelia-specific monoclonal antibody H9724 reacted with an epitope in the central region of the flagellar protein (amino acids 205 to 226), which is heterologous to the amino acid sequences of other bacterial flagellins. This epitope was not recognized by human sera with antibodies to Treponema pallidum, sera of healthy individuals, or sera from patients with stage I or II of Lyme disease.
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