title: Isolation of potent and specific trypsin inhibitors from a DNA-encoded chemical library.
abstract: Collections of chemical compounds, individually attached to unique DNA fragments serving as amplifiable identification bar codes, are generally referred to as "DNA-encoded chemical libraries". Such libraries can be used for the de novo isolation of binding molecules against target proteins of interest. Here, we describe the synthesis and use of a DNA-encoded library based on benzamidine analogues, which allowed the isolation of a trypsin inhibitor with an IC(50) value of 3.0 nM, thus representing a >10 000-fold potency improvement compared to the parental compound. The novel trypsin inhibitor displayed an excellent selectivity toward other serine proteases. This study indicates that DNA-encoded libraries can be used for the facile "affinity maturation" of suboptimal binding compounds, thus facilitating drug development.
authors.affiliation: Institute of Pharmaceutical Sciences, ETH Zürich, Zürich, Switzerland. luca.mannocci@philochem.ch
authors.forename: Luca
authors.initials: L
authors.lastname: Mannocci
authors.forename: Samu
authors.initials: S
authors.lastname: Melkko
authors.forename: Fabian
authors.initials: F
authors.lastname: Buller
authors.forename: Ilona
authors.initials: I
authors.lastname: Molnàr
authors.forename: Jean-Paul Gapian
authors.initials: JP
authors.lastname: Bianké
authors.forename: Christoph E
authors.initials: CE
authors.lastname: Dumelin
authors.forename: Jörg
authors.initials: J
authors.lastname: Scheuermann
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D001483:Base Sequence; D001550:Benzamidines / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D020128:Inhibitory Concentration 50; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D014357:Trypsin / Q000378:metabolism*; D014361:Trypsin Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001550:Benzamidines; D054852:Small Molecule Libraries; D014361:Trypsin Inhibitors; D004247:DNA; D014357:Trypsin; C032157:benzamidine