DESIGN AND SYNTHESIS OF POLY L PROLINE II PEPTIDE MIMICS

描述：拟议研究的目标是设计和综合 多肽模拟L-脯氨酸II型二级结构(PPII)。 这将通过合成修饰氨基酸(PTAA)来实现。 当它们结合在一起时，在溶液中采用PPII构象。 PTAA将允许合成PPII螺旋模拟物，包括虚拟 所需的任何氨基酸序列(天然或非天然)。这种多功能性 将被用于靶向erbB2介导的乳腺转化 癌症目前在癌症化疗中很受关注。就其本身而言 将合成特定的PPII模拟物作为第一个 ErbB2介导信号转导的三个步骤：1)erbB2/erbB3 转磷酸化；2)erbB2/erbB3与Scr同源物的关系 磷脂酰肌醇3激酶P85亚单位的(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对应的侧链官能团的PTAA， Leu、Glu、Arg、Phe、Tyr和pTyr以及它们的非自然变体 氨基酸。每个目标的共识识别序列 然后，系统将指导多肽模拟物的设计，作为这些化合物的抑制剂 ErbB2介导的信号转导步骤。因此，从这些PTAA中：1)PPII模拟 围绕序列Glu-Tyr-Met-Pro-Met-Val将被合成为 ERBB2酪氨酸激酶抑制剂；2)包含序列的PPII模拟物 PTyr-Met-Pro-Met-Ser将被合成为P85SH2结构域结合体；3)PPII 包含Arg-Pro-Leu-Pro-Pro-Arg-Pro-Ala序列的模拟物将是 合成为P85SH3结构域结合剂。

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.