Peptide inhibitors of the mitogen-activated protein kinase pathway: A structure-mimetic peptide corresponding to the conserved inter-DFC-APE region in the kinase domain

The signal transduction pathway mediated by mitogen-activated protein kinas es is an attractive target for the design of pharmacologically effective in hibitors. Two specific cell permeant small molecule inhibitors of this path way have been reported. However, under certain circumstances, nonpermeable inhibitors, such as neutralizing antibodies and peptide inhibitors, are als o useful. We present here a novel approach for such peptide inhibitor desig n. The procedure is based on the synthesis of a structure mimetic peptide c orresponding to a short peptide segment in the target molecule. The results obtained so far show that a peptide designed in such a way is an effective inhibitor of the pathway. The possible application of such peptides and an tipeptide antibodies as probes for protein kinase regulation mechanisms is also evaluated. (C) 1999 Elsevier Science Inc. All rights reserved.