DESIGN AND SYNTHESIS OF POLY L PROLINE II PEPTIDE MIMICS

聚L-脯氨酸II肽模拟物的设计与合成

• 批准号: 2630744
• 负责人: JOSE S MADALENGOITIA
• 金额: $ 11.08万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2630744
• 关键词: X ray crystallography; antineoplastics; drug design /synthesis /production; enzyme inhibitors; homopeptide; nuclear magnetic resonance spectroscopy; peptide analog; peptide chemical synthesis; proline; protein binding; protein purification; protein sequence; protein structure function; structural biology; synthetic peptide

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.

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。 这将通过合成修饰的氨基酸（PTAA）来实现。 当它们偶联在一起时，在溶液中采用PPII构象。 PTAA将允许PPII螺旋模拟物的合成， 所需的任何氨基酸序列（天然或非天然）。 这种多功能性 将用于靶向erbB 2介导的乳腺癌细胞转化 这是目前癌症化疗中感兴趣的癌症。 因此 特定的PPII模拟物将被合成为第一种的每一种的抑制剂， erbB 2介导的信号转导过程分为三个步骤：1）erbB 2/erbB 3 erbB 2/erbB 3与Scr同源性2相关 (SH2)磷脂酰肌醇3激酶p85亚基的结构域 （P13 K），和3）P13 K Src同源性3（SH 3）结构域与 下游效应器。 这些目标将首先实现 合成具有对应于Met的侧链官能团的PTAA， Leu、Glu、Arg、Phe、Tyr和pTyr以及这些的非天然变体 个氨基酸 针对每个靶分子的共有识别序列 然后，系统将指导肽模拟物的设计， erbB 2介导的信号传导步骤。 因此，从这些PTAA：1）PPII模拟物 包含序列Glu-Tyr-Met-Pro-Met-Val的氨基酸将被合成， erbB 2酪氨酸激酶抑制剂; 2）PPII模拟物，包括序列 pTyr-Met-Pro-Met-Ser将被合成为p85 SH 2结构域结合剂; 3）PPII 包含序列Arg-Pro-Leu-Pro-Pro-Arg-Pro-Ala的模拟物将是 作为p85 SH 3结构域结合剂合成。