This proposal details the exploitation of isozyme-selective protein kinase C (PKC) activation as a fundamentally new approach to the design of novel therapeutic agents. The PKC family of serine/threonine kinases is composed of at least 11 structurally related isozymes that participate in a variety of cellular signal transduction pathways. By playing critical regulatory roles in human diseases such as cancer, diabetes and Alzheimer's dementia, the PKC isozymes are attractive, the PKC isozymes are attractive targets for chemotherapeutic intervention. A recently identified isozyme-selective epsilonPKC agonist has demonstrated significant in vivo cardioprotection from ischemia related necrosis and serves as the basis for molecular design efforts toward new treatments for cardiovascular disease. Techniques such as organic synthesis, nuclear magnetic resonance (NMR) spectroscopy and molecular modeling will be utilized in the development of peptidomimetic, isozyme-selective PKC agonists based on this octapeptide lead compound. During the course of this research, several specific aims will be addressed: 1) the development of accurate methods for the assessment of epsilonPKC activation,, 2) the identification of the active core required for epsilonPKC agonism and 3) the elaboration of this active core onto bioavailable peptidomimetic scaffold. Future treatments for cancer, diabetes and Alzheimer's dementia may rely on the demonstration of a general approach to the isozyme-selective modulation of PKC activity.
