Design and synthesis of a beta-strand inducer. Application to ICAM-1/LFA-1 mediated cellular adhesion.
The binding of lymphocyte function associated antigen (LFA-1) to intercellular adhesion molecule (ICAM-1) is responsible for several types of cellular adhesion. Amino-acid substitution mutants of ICAM-1 have established the importance of several sequences in this protein. We selected the binding region of Glu34 for further study. One published model of domain 1 placed Glu34 near the end of a beta-strand. We designed and synthesized three tripeptide derivatives centered on the Glu34 sequence and attached a platform which, through hydrogen bonds, induces a rigid beta-strand conformation. Variable temperature NMR methods coupled with NOESY 2D NMR data enabled determination of the solution conformation of these compounds.
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania, USA.
W F
WF
Michne
J D
JD
Schroeder
D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D004121:Dimethyl Sulfoxide; D015195:Drug Design; D018799:Intercellular Adhesion Molecule-1 / Q000737:chemistry*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D013696:Temperature
D000634:Aminoquinolines; D016169:Lymphocyte Function-Associated Antigen-1; D009842:Oligopeptides; D010446:Peptide Fragments; D018799:Intercellular Adhesion Molecule-1; D004121:Dimethyl Sulfoxide