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.
Michne
W F
WF
Department of Medicinal Chemistry, Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania, USA.
Schroeder
J D
JD
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