The goal of the proposed research is the design and synthesis of peptide mimics of the poly-L-proline type II secondary structure (PPII). This will be accomplished by the synthesis of modified amino acids (PTAAs) which, when coupled together, adopt the PPII conformation in solution. PTAAs will allow the synthesis of PPII helix mimics encompassing virtually any sequence o amino acids desired (natural or unnatural). This versatility will be used to target the erbB2 mediated transformation in mammary carcinomas which is currently of interest in cancer chemotherapy. As such specific PPII mimics wil be synthesized as inhibitors of each of the first three steps in erbB2 mediate signal transduction: 1) erbB2/erbB3 transphosphorylation; 2) erbB2/erbB3 association with the Scr homology 2 (SH2) domains of the p85 subunit of the phosphotidylinositol 3 kinase (P13K), and 3) association of the P13K Src homology 3 (SH3) domain with downstream effectors. These goals will be accomplished by first synthesizing PTAAs possessing side chain functionality corresponding to Met, Leu, Glu, Arg, Phe, Tyr, and pTyr as well as unnatural variants of these amino acids. The consensus recognition sequences for each of the target systems will then guide the design of peptide mimics as inhibitors of these steps in erbB2 mediated signaling. Thus, from these PTAAs: 1) PPII mimics encompassing the sequence Glu-Tyr-Met-Pro-Met-Val will be synthesized a erbB2 tyrosine kinase inhibitors; 2) PPII mimics encompassing the sequence pTyr-Met-Pro-Met-Ser will be synthesized as p85 SH2 domain binders; 3) PPII mimics encompassing the sequence Arg-Pro-Leu-Pro-Pro-Arg-Pro-Ala will be synthesized as p85 SH3 domain binders.
