DESIGN AND SYNTHESIS OF POLY L PROLINE II PEPTIDE MIMICS

描述：拟议研究的目标是设计和合成 聚-L-脯氨酸 II 型二级结构 (PPII) 的肽模拟物。 这将通过合成修饰氨基酸（PTAA）来实现 当它们耦合在一起时，在溶液中采用 PPII 构象。 PTAA 将允许合成 PPII 螺旋模拟物，几乎涵盖 任何所需的氨基酸序列（天然或非天然）。 这种多功能性 将用于靶向 erbB2 介导的乳腺转化 目前人们对癌症化疗感兴趣的癌症。 因此 特定的 PPII 模拟物将被合成作为每个第一个的抑制剂 erbB2 介导信号转导的三个步骤：1) erbB2/erbB3 转磷酸化； 2) erbB2/erbB3 与 Scr 同源性 2 的关联 磷脂酰肌醇 3 激酶 p85 亚基的 (SH2) 结构域 (P13K)，以及 3) P13K Src 同源 3 (SH3) 结构域与 下游效应器。 这些目标将首先实现 合成具有与Met相对应的侧链功能的PTAA， Leu、Glu、Arg、Phe、Tyr 和 pTyr 以及这些的非天然变体 氨基酸。 每个目标的共有识别序列 然后系统将指导肽模拟物的设计作为这些抑制剂 erbB2 介导的信号传导步骤。 因此，从这些 PTAA 中：1) PPII 模拟物 包含序列 Glu-Tyr-Met-Pro-Met-Val 将被合成 erbB2酪氨酸激酶抑制剂； 2) PPII 模拟物包含序列 pTyr-Met-Pro-Met-Ser 将被合成为 p85 SH2 结构域结合物； 3）PPII 包含序列 Arg-Pro-Leu-Pro-Pro-Arg-Pro-Ala 的模拟物将是 合成为 p85 SH3 结构域结合物。

DESCRIPTION: 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.