title: Discovery of TNF inhibitors from a DNA-encoded chemical library based on diels-alder cycloaddition.
abstract: DNA-encoded chemical libraries are promising tools for the discovery of ligands toward protein targets of pharmaceutical relevance. DNA-encoded small molecules can be enriched in affinity-based selections and their unique DNA "barcode" allows the amplification and identification by high-throughput sequencing. We describe selection experiments using a DNA-encoded 4000-compound library generated by Diels-Alder cycloadditions. High-throughput sequencing enabled the identification and relative quantification of library members before and after selection. Sequence enrichment profiles corresponding to the "bar-coded" library members were validated by affinity measurements of single compounds. We were able to affinity mature trypsin inhibitors and identify a series of albumin binders for the conjugation of pharmaceuticals. Furthermore, we discovered a ligand for the antiapoptotic Bcl-xL protein and a class of tumor necrosis factor (TNF) binders that completely inhibited TNF-mediated killing of L-M fibroblasts in vitro.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zurich, Switzerland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Buller
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jörg
authors.initials: J
authors.lastname: Scheuermann
authors.forename: Juliane
authors.initials: J
authors.lastname: Schäfer
authors.forename: Peter
authors.initials: P
authors.lastname: Bühlmann
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000737:chemistry*; D015195:Drug Design; D057166:High-Throughput Screening Assays; D055767:Immobilized Proteins / Q000378:metabolism; D008024:Ligands; D051379:Mice; D054852:Small Molecule Libraries; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D055767:Immobilized Proteins; D008024:Ligands; D054852:Small Molecule Libraries; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D051020:bcl-X Protein; D004247:DNA