title: Application of encoded library technology (ELT) to a protein-protein interaction target: discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists.
abstract: The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Kollmann
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Bai
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Ching-Hsuan
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Hongfang
authors.initials: H
authors.lastname: Yang
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lind
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Skinner
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Israel
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Cuozzo
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Morgan
authors.affiliation: Immune Disease Institute, Children's Hospital Boston, Harvard Medical School, Program in Cellular and Molecular Medicine, Department of Biological Chemistry and Molecular Pharmacology, 3 Blackfan Circle, Rm. 3100, Boston, MA 02115, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yuki
authors.affiliation: Immune Disease Institute, Children's Hospital Boston, Harvard Medical School, Program in Cellular and Molecular Medicine, Department of Biological Chemistry and Molecular Pharmacology, 3 Blackfan Circle, Rm. 3100, Boston, MA 02115, USA.
authors.forename: Can
authors.initials: C
authors.lastname: Xie
authors.affiliation: Immune Disease Institute, Children's Hospital Boston, Harvard Medical School, Program in Cellular and Molecular Medicine, Department of Biological Chemistry and Molecular Pharmacology, 3 Blackfan Circle, Rm. 3100, Boston, MA 02115, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
authors.affiliation: Immune Disease Institute, Children's Hospital Boston, Harvard Medical School, Program in Cellular and Molecular Medicine, Department of Biological Chemistry and Molecular Pharmacology, 3 Blackfan Circle, Rm. 3100, Boston, MA 02115, USA.
authors.forename: Motomu
authors.initials: M
authors.lastname: Shimaoka
authors.affiliation: GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA. Electronic address: ghotas.x.evindar@gsk.com.
authors.forename: Ghotas
authors.initials: G
authors.lastname: Evindar
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D016169:Lymphocyte Function-Associated Antigen-1; D054852:Small Molecule Libraries
keywords: Affinity-based selections; DNA-encoded libraries; Encoded Library Technology; Intercellular Adhesion Molecule 1; Lymphocyte Function-associated Antigen 1; Protein-Protein Interactions