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Unformatted text preview: Single-bead, Single-molecule, Single-cell Fluorescence Technologies for Drug Screening and Target Validation M ARTIN H INTERSTEINER AND M ANFRED A UER Novartis Institutes for BioMedical Research, Innovative Screening Technologies, Vienna, Austria According to many current reports, the pharmaceutical business will hit a wall over the next few years. The generic competition is expected to wipe out a double-digit billion-dollar amount from top companies’ annual sales between 2007 and 2012 ( Wall Street Journal , online, December 6, 2007). The industry’s science engine has stalled, new blockbusters are lacking, and patent expirations are a big problem. Also, the U.S. Food and Drug Administration is pulling back on approvals, requesting larger safety studies. Among the different approaches taken throughout the industry to improve productivity and to reduce the attrition rate of compounds in the drug discovery process, an extended application of quantitative biology and biophysical methods is ranked very high. Fluorescence spectroscopy and imaging represented the main detection technologies for assays and screening methods in recent years. Today, label-free detection methods, such as isothermal titration calorimetry, differential scanning calorimetry, tandem mass spectrometry (MS n ), light scattering, or interferometry, start to provide viable alternative readouts for physicochemical characterizationofleadsandhitlisttriaging.However,themultidimensionalnatureoffluorescence along with its high sensitivity and single-molecule resolution remains an unparalleled source of molecular parameters to extract all different kinds of information on molecules and ligand–protein complexes in solution. Although fluorescence-based methods are currently applied throughout the different stages of the industrial drug discovery process, they are usually applied in an unconnected way. We have developed a fully integrated hit and lead discovery process combining bead-based synthesis and screening methods with confocal fluorescence microspectroscopy. The primary on- bead screening process provides fluorescent ligands that after a multistep characterization process ultimatelyleadstofullymechanisticallycharacterizedcellularlyvalidatedbindersandinhibitorsof target protein interactions. The unlabeled small-molecular inhibitors represent chemical starting points in drug discovery and target validation. Key words: high-throughput screening; affinity selection; chemical biology; bead-based screening; one-bead-one-compound; confocal spectroscopy; drug discovery Introduction Current Challenges in Drug Discovery and Strategies to Reduce Attrition Rates of Compounds from Research to Market Placement Since the early days of serendipitous drug discover- ies and soil screening, constant scientific and techno- logical advances have changed the process by which new medicines are generated. Today this process is highly formalized, standardized, and categorized into Address for correspondence: Univ. Doz. Dr. Manfred Auer, Novartis In-Address for correspondence: Univ....
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This note was uploaded on 07/11/2010 for the course SPECTOGRAP 545 taught by Professor Gdf during the Spring '10 term at AIB College of Business.
- Spring '10