title: Functional consequences of engagement of the T cell receptor by low affinity ligands.
abstract: The mechanisms involved in TCR antagonism by Ag analog/MHC have been analyzed. A detailed structure-activity relationship study indicated that modification of any of the major T cell contact residues of the peptide molecule can yield a powerful antagonist. It was also shown that as the analog structure increased in similarity to the Ag, the capacity to antagonize Ag-TCR interaction increased up to the point that the analogs themselves became antigenic. These data strongly suggest an affinity-related mechanism whereby a certain affinity is required for signaling through the TCR, and that below this level there can be sufficient affinity to engage the receptor such that triggering does not occur and antagonism can be detected. Taking advantage of this information, antagonist peptides active down to the 10 nM range were engineered. Thus, this approach demonstrates for the first time a rational approach to designing effective, selective low m.w. compounds with high potential in treatment of allergies and autoimmune diseases.
authors.affiliation: Cytel, San Diego, CA 92121.
authors.forename: J
authors.initials: J
authors.lastname: Alexander
authors.forename: K
authors.initials: K
authors.lastname: Snoke
authors.forename: J
authors.initials: J
authors.lastname: Ruppert
authors.forename: J
authors.initials: J
authors.lastname: Sidney
authors.forename: M
authors.initials: M
authors.lastname: Wall
authors.forename: S
authors.initials: S
authors.lastname: Southwood
authors.forename: C
authors.initials: C
authors.lastname: Oseroff
authors.forename: T
authors.initials: T
authors.lastname: Arrhenius
authors.forename: F C
authors.initials: FC
authors.lastname: Gaeta
authors.forename: S M
authors.initials: SM
authors.lastname: Colón
mesh_terms: D000596:Amino Acids / Q000276:immunology / Q000494:pharmacology; D001667:Binding, Competitive; D006684:HLA-DR Antigens / Q000378:metabolism; D006388:Hemagglutinins / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D010446:Peptide Fragments / Q000494:pharmacology*; D011485:Protein Binding; D015202:Protein Engineering; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D006684:HLA-DR Antigens; D006388:Hemagglutinins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell