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2 results on '"Daniel Schlatter"'

1. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

Author

Nadine Ruderisch, Daniel Schlatter, Andreas Kuglstatter, Wolfgang Guba, Sylwia Huber, Carlo Cusulin, Jörg Benz, Arne Christian Rufer, Joerg Hoernschemeyer, Christophe Schweitzer, Tina Bülau, Achim Gärtner, Eike Hoffmann, Jens Niewoehner, Christoph Patsch, Karlheinz Baumann, Hansruedi Loetscher, Eric Kitas, and Per-Ola Freskgård

Subjects
BACE1, Alzheimer's disease, Blood brain barrier, CNS delivery, Medicine, Medicine (General), R5-920
Abstract

Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ) antibodies and secretase inhibitors. However, the blood-brain barrier (BBB) limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS) technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

Published
2017
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2. The Difference Interferometer: Application as a Direct Immunosensor

Author

Jurg Hurst, Ch. Fattinger, Richard Barner, Josef Hübscher, Walter Huber, Francis Müller, C. Mangold, Daniel Schlatter, and H. Koller

Subjects
Detection limit, Analyte, Chromatography, Reaction rate constant, Antigen, biology, Chemistry, Monolayer, biology.protein, Analytical chemistry, Antibody, Orders of magnitude (mass), Dilution
Abstract

This paper describes the application of a novel sensor technology for the concentration determination of biologically and diagnostically relevant analytes with high sensitivity and for the investigation of biological recognition reactions such as antibody antigen reactions. On the basis of the interaction between an anti human IgG and a human IgG a broad dynamic concentration range extending over six orders of magnitude and a detection limit of 1×10-11 M dissolved antibody are demonstrated to be relevant for the determination of concentrations with this sensor system. The effective surface concentration obtained at this dilution is 19 pg/mm2, which corresponds to less than 4 per mille of a possible monolayer. Measurements of the clinically relevant hepatitis B surface antigen show the same high sensitivity - 2×10-13 M antigen could be detected even in undiluted human serum. The most interesting feature of biospecific interaction analysis with this sensor system is the fact that one can observe the course of a binding reaction between two molecules in real time. Based on the anti human IgG / human IgG model system we demonstrate the determination of equilibrium as well as rate constants of such reactions directly from the binding data.

Published
1992

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