Single Bead Labeling Method for Combining Confocal Fluorescence On-Bead Screening and Solution Validation of Tagged One-Bead One-Compound Libraries

Martin Hintersteiner, Thierry Kimmerlin, Frank Kalthoff, Markus Stoeckli, Geraldine Garavel, Jan-Marcus Seifert, Nicole-Claudia Meisner, Volker Uhl, Christof Buehler, Thomas Weidemann, Manfred Auer

Research output: Contribution to journalArticlepeer-review

Abstract

Screening of one-bead one-compound libraries by incubating beads with fluorescently labeled target protein requires isolation and structure elucidation of a large number of primary hit beads. However, the potency of the identified ligands is only revealed after time consuming and expensive larger scale resynthesis and testing in solution. Often, many of the resynthesized compounds turn out to be weak target binders in solution due to large differences between surface and solution binding affinities. For an industry style high-throughput screening (HTS) process a high false positive rate is detrimental. We have therefore combined single bead and single molecule/single cell techniques into an integrated HTS process in which the picomole amount of substance contained on one isolated hit bead is sufficient for quality control, structure determination, and precise affinity determination to the target protein in solution.

Original languageEnglish
Pages (from-to)724-735
Number of pages12
JournalChemistry and Biology
Volume16
Issue number7
DOIs
Publication statusPublished - 31 Jul 2009

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