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: 6173435
• 负责人: JOSE S MADALENGOITIA
• 金额: $ 11.75万
• 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/6173435
• 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：提出的研究目标是设计和合成