title: A small-molecule antagonist of LFA-1 blocks a conformational change important for LFA-1 function.
abstract: Lymphocyte function-associated antigen (LFA)-1/intercellular adhesion molecule (ICAM)-1 interactions mediate several important steps in the evolution of an immune response. LFA-1 is normally expressed in a quiescent state on the surface of leukocytes and interacts weakly with its ligands ICAM-1, -2, and -3. LFA-1 activity may be regulated by receptor clustering and by increasing the affinity of LFA-1 for its ligands. Affinity modulation of LFA-1 has been shown to occur via a conformational change in the LFA-1 heterodimer that can be detected by using monoclonal antibody 24 (mAb24). We have recently described a small-molecule antagonist of LFA-1, BIRT 377, that demonstrates selective in vitro and in vivo inhibition of LFA-1/ICAM-1-mediated binding events. We now demonstrate that BIRT 377 blocks the induction of the mAb24 reporter epitope on LFA-1 on the surface of SKW-3 cells treated with various agonists known to induce high-affinity LFA-1. These data imply that BIRT 377 exerts its inhibitory effects by preventing up-regulation of LFA-1 to its high-affinity conformation.
authors.affiliation: Department of Biology and. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. jwoska@rdg.boehringer-ingelheim.com
authors.forename: J R
authors.initials: JR
authors.lastname: Woska
authors.forename: D
authors.initials: D
authors.lastname: Shih
authors.forename: V R
authors.initials: VR
authors.lastname: Taqueti
authors.forename: N
authors.initials: N
authors.lastname: Hogg
authors.forename: T A
authors.initials: TA
authors.lastname: Kelly
authors.forename: T K
authors.initials: TK
authors.lastname: Kishimoto
mesh_terms: D000494:Allosteric Regulation; D002448:Cell Adhesion; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D011487:Protein Conformation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C400461:BIRT 377; D000939:Epitopes; D007093:Imidazoles; D048289:Imidazolidines; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D018799:Intercellular Adhesion Molecule-1