DESIGN & SYNTHESIS OF PEPTIDOMIMETIC COMPOUNDS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research is centered at the interface of organic chemistry and chemical biology. From a philosophy that biological systems may be studied from an organic chemist''s perspective and using the tools of synthesis, come new ideas which help advance our knowledge of chemical biology. In turn, problems encountered in the synthesis of agents designed to probe biological systems often necessitate the development of new synthetic methodology. Fundamental research in these two areas thus strengthen and complement each other. One of our main peptidomimetic projects is focused on the design and synthesis of mimics of the poly-L-proline type II (PPII) secondary structure. The synthesis of PPII mimics that act as agonists or antagonists of these cell signaling pathways are useful in unraveling the complex signaling cascades as well as being potential starting points for pharmaceuticals. Our PPII design strategy is guided by an understanding of the conformational proper tie s of all-proline containing peptides in which the angle phi is restricted to ca. -75: by the constraints of the pyrrolidine ring while the psi angle is constrained to ca. 145: by the minimization of pseudo-A(1,3) strain. We utilize these conformational constraint elements to synthesize PPII mimics from templated amino acids (PTAAs). Our laboratory has developed an extensive program focused on the synthesis of PTAAs as well as the development of PPII mimic combinatorial libraries.