Cellular signal transduction through protein kinase C (PKC) is coupled to normal cell function but also figures in therapeutic strategies for the treatment of cancer, neuropathic pain, ischemia, diabetes, and other diseases. We are trying to understand how PKC recognizes its activators as a first step in the rational design of therapeutic agents for the above diseases. In collaboration with the Irie Group at Kyoto, we have now synthesized all of the PKC regulatory domain peptides and have demonstrated that they bind as well as the whole proteins. These robotic syntheses require in excess of 100 steps but proceed in overall yields of > 15%! We are now using the resultant receptor surrogates to understand the specifics of recognition at the regulatory domain and in mechanistic, drug design, and combinatorial studies. This effort is being conducted in collaboration with other projects directed at understanding the mode of action of new therapeutic candidates.
