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RNA-controlled synthesis of peptides via peptidyl transfer reactions with peptide-nucleic acid conugates

通过肽-核酸缀合物的肽基转移反应进行 RNA 控制的肽合成

基本信息

批准号：
225213878
负责人：
Professor Dr. Oliver Seitz
金额：
--
依托单位：
Institut für Chemie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/225213878?language=en
关键词：
RNA controlled synthesis peptides via

项目摘要

It is the aim to develop a reaction, which proceeds only when a specific RNA sequence is present and leads to the formation of a biologically active compound. This is accomplished by means of a RNA-triggered peptidyl transfer reaction, which bears resemblance to a key step in ribosomal peptide synthesis. The reaction involves a donor peptide, which is connected via a thioester bond to a peptide nucleic acid (PNA) unit. A second peptide-PNA conjugate offers a reactive 1,2- or 1,3-aminothiol structure at the N-terminal end and serves as acceptor. The two conjugates bind adjacently to a complementary RNA template. This triggers the intramolecular transfer of the donor onto the acceptor peptide. A new peptide bond is formed in a native chemical ligation like reaction. The prerequisites for efficient peptidyl transfer are examined by varying the architecture of the RNA templates, the length of the donor and acceptor peptides as well as the structure of the thioesters involved. The RNA-triggered peptidyl transfer may provide new opportunities for the development of a) artificial feedback loops in synthetic biology and b) cell type specific, personalized bioactive compounds. It is the long-term objective to hijack cell endogenous RNA molecules and use the RNA sequence information for the programmed formation of compounds that modulate signal transduction e.g. in cancer cells. The RNA templates can act as catalysts which trigger the formation of many peptide molecules per template. The achievable turnover rate is an important reaction parameter given that the RNA target of interest may occur at low abundance. The in situ formed peptides will be used to inhibit Bcl-xL; a protein that prevents apoptosis in cancer cells. Further efforts are directed to the RNA-induced synthesis of a phosphopeptide that inhibits the Signal Transduction and Activator of Transcription 3 (Stat3). The ability to translate RNA information into protein inhibition will be assessed in protein binding assays which involve recombinant proteins and proteins in cell lysates.

其目的是开发一种反应，该反应仅在特定RNA序列存在时进行，并导致形成生物活性化合物。这是通过RNA触发的肽基转移反应完成的，这与核糖体肽合成中的关键步骤相似。该反应涉及供体肽，其通过硫酯键连接到肽核酸（PNA）单元。第二种肽-PNA缀合物在N-末端提供反应性1，2-或1，3-氨基硫醇结构并用作受体。两种缀合物相邻地结合互补RNA模板。这触发供体分子内转移到受体肽上。在天然化学连接样反应中形成新的肽键。通过改变RNA模板的结构、供体和受体肽的长度以及所涉及的硫酯的结构来检查有效肽基转移的先决条件。RNA触发的肽基转移可以为开发a）合成生物学中的人工反馈环和B）细胞类型特异性的个性化生物活性化合物提供新的机会。长期目标是劫持细胞内源性RNA分子并使用RNA序列信息来编程形成调节例如癌细胞中的信号转导的化合物。RNA模板可以充当催化剂，其触发每个模板形成许多肽分子。考虑到目标RNA靶标可能以低丰度存在，可实现的周转率是重要的反应参数。原位形成的肽将用于抑制Bcl-xL;一种防止癌细胞凋亡的蛋白质。进一步的努力针对RNA诱导的磷酸肽合成，该磷酸肽抑制信号转导和转录激活因子3（Stat 3）。将在涉及重组蛋白和细胞裂解物中蛋白的蛋白结合试验中评估将RNA信息转化为蛋白抑制的能力。