Transfer of a protein binding epitope to a minimal designed peptide

Results from protein mutagenesis and x-ray crystallographic studies of the multidomain protein Vascular Cell Adhesion Molecule (VCAM) were used to des ign cyclic octapeptides that retain the critical structural and binding ele ments of the epitope of VCAM in the interaction with the integrin alpha(4)b eta(1) (VLA-4). Changes in the activities of peptide analogues correlated w ith the relative activities of protein mutants of VCAM, and predicted the p roperties of two new mutants that bound alpha(4)beta(1) with improved affin ity vs wild type protein. The nmr structures of two peptides revealed a hig h degree of similarity to the structure of the VCAM binding epitope. These results demonstrate that a compact binding epitope identified I ia protein structure-function studies may be transferred to a synthetically accessible small peptide with the key structure-activity relationships intact. (C) 19 98 John Wiley & Sons, Inc.