title: Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule.
abstract: The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.
authors.affiliation: Department of Bioorganic Chemistry, Genentech, One DNA Way, South San Francisco, CA 94080, USA. trg@gene.com
authors.forename: T R
authors.initials: TR
authors.lastname: Gadek
authors.forename: D J
authors.initials: DJ
authors.lastname: Burdick
authors.forename: R S
authors.initials: RS
authors.lastname: McDowell
authors.forename: M S
authors.initials: MS
authors.lastname: Stanley
authors.forename: J C
authors.initials: JC
authors.lastname: Marsters
authors.forename: K J
authors.initials: KJ
authors.lastname: Paris
authors.forename: D A
authors.initials: DA
authors.lastname: Oare
authors.forename: M E
authors.initials: ME
authors.lastname: Reynolds
authors.forename: C
authors.initials: C
authors.lastname: Ladner
authors.forename: K A
authors.initials: KA
authors.lastname: Zioncheck
authors.forename: W P
authors.initials: WP
authors.lastname: Lee
authors.forename: P
authors.initials: P
authors.lastname: Gribling
authors.forename: M S
authors.initials: MS
authors.lastname: Dennis
authors.forename: N J
authors.initials: NJ
authors.lastname: Skelton
authors.forename: D B
authors.initials: DB
authors.lastname: Tumas
authors.forename: K R
authors.initials: KR
authors.lastname: Clark
authors.forename: S M
authors.initials: SM
authors.lastname: Keating
authors.forename: M H
authors.initials: MH
authors.lastname: Beresini
authors.forename: J W
authors.initials: JW
authors.lastname: Tilley
authors.forename: L G
authors.initials: LG
authors.lastname: Presta
authors.forename: S C
authors.initials: SC
authors.lastname: Bodary
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D017453:Dermatitis, Irritant / Q000188:drug therapy; D004139:Dinitrofluorobenzene; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry; D016296:Mutagenesis; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015091:beta-Alanine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C448301:2-(4-(3-hydroxy-3-(hydroxyphenyl)propyl)-2,6-dichlorophenyl)carbomylamino-3-((thiophen-2-yl)carbonylamino)propanoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D013876:Thiophenes; D015091:beta-Alanine; D018799:Intercellular Adhesion Molecule-1; D016572:Cyclosporine; D004139:Dinitrofluorobenzene