SIGNAL TRANSDUCTION PROBED BY CONSOLIDATED LIGANDS

We shall develop reagents to bind to significant elements of proteins involved in intracellular transduction via their Src Homology (SH) 2, and SH3 domains. The proteins involved, Grb2, Lck, Hck, Crk, Abl, and STAT1 are central to growth factor mediated cell transformation, the immune response, causation of chronic myologenous leukemia, and the responses to cytokines. The issues of binding site organization, design of inhibitors, and delineation of pathways is then likely to be useful in many specific pathological investigations, including cancer, diabetes, autoimmune disorders, and response to infections. Reagents developed from these ligands may have broad investigational, and potentially therapeutic, application. The approach used consolidated ligand, in which the natural multiple binding sites of signal transducing proteins, containing multiple domains, will be complemented by dual ligands tethered together by specifically designed linkers. This approach has been shown to be practical already for Abl SH (32). Small combinatorial peptide libraries based on structural insights, with topological and liker length variation will be screened by biochemical means for binding to the target, and those binding strongly will be subject to further development, by rational and combinatorial methods.