基于氟化硼二吡咯（BODIPY）的荧光β-转角(β-turn)模拟物的设计、合成及其用于多肽β-折叠(β-sheet)结构的构建与生物活性检测

As one of the most typical secondary structures, β-sheet has a crucial influence on the function of proteins, using fluorescence techniques to study the interaction between β-sheets and proteins (receptors) has great scientific significance and practical value, the synthesis of protein secondary structure mimics is also the difficulty in peptide chemistry. Using unnatural amino acids as templates to induce β-sheet structure in small peptides is most advantageous, because these templates eliminated most of the entropic penalty associated with chain reversal due to their U shape, however, to the best of our knowledge, none of these compounds have been reported to be fluorescent. This project is firstly proposed using 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) as research object for the development of fluorescent β-turn mimics, since it not only would lead to short conformationally restricted peptides, but also could be easily detected and studied by fluorescence techniques. On this basis, designing and synthesizing different bioactive β-sheet mimics to explore their biomedical applications as fluorescent probes. The concrete content includes: Design and synthesis of fluorescent β-turn mimics based on BODIPY; Synthesizing somatostatin analogues, peptide P3378-1 and ZD2-1 as examples to explore the application prospect of fluorescent β-turn mimics, the binding ability of fluorescent peptides to their receptors were studied by fluorescence anisotropy and their abilities as a fluorescent probe for detecting tumor cells were investigated by fluorescence imaging technology; Finally, generalize this technology to research other field of peptide-protein, protein-protein interactions for providing useful information in designing potential drug candidates.

β–折叠结构对蛋白质的功能具有重要影响，利用荧光技术研究β–折叠结构与蛋白质（受体）的相互作用具有极大的科学意义和实用价值，它的模拟合成也是多肽化学研究的难点。利用非天然氨基酸形成U型结构模拟β–转角，进而诱导β–折叠的形成是其人工合成最理想的方法，然而在众多β–转角模拟物中，无人采用荧光化合物。本项目首次采用具有优良荧光性质的氟化硼二吡咯（BODIPY）模拟β–折叠结构中的β–转角单元，在此基础上设计、合成多个具有β–折叠结构的生物活性分子，探索其作为荧光探针在生物医药方面的应用前景。主要内容包括：对BODIPY结构进行设计，合成基于BODIPY的荧光β–转角模拟物；以合成somatostatin analogues，多肽P3378-1和ZD2-1为例，通过荧光技术研究其生物活性，探索得到的荧光β–转角模拟物的应用前景；将此技术模板化，推广运用到其它多肽–蛋白、蛋白–蛋白相互作用领域。

β–折叠结构对蛋白质的功能具有重要的影响，利用荧光技术研究β–折叠结构与蛋白质（受体）的相互作用具有极大科学意义和实用价值，它的模拟合成也是多肽化学研究的难点。利用具有优良荧光性质的氟化硼二吡咯（BODIPY）模拟β–折叠结构中的β–转角单元，在此基础上设计、合成具有β-sheet 结构的活性多肽类似物分子，通过荧光方法研究多肽与受体间的相互作用。本项目将基于BODIPY的β–转角模拟物用于以下三部分多肽的合成：第一，合成含有BODIPY的somatostatin analogues，通过HPLC，HRMS，NMR，CD 等谱图确认其结构。含有BODIPY的somatostatin analogues存在β–sheet结构，荧光各向异性的研究发现这些多肽与somatostatin的五类受体蛋白sst1，sst2，sst3，sst4，sst5均具有相互作用，选择性一般。第二，合成含有BODIPY 的多肽P3378-1，用于研究其与分泌型丛生蛋白（sCLU）的相互作用，研究表明BODIPY的引入会影响其生物活性，所以这类多肽的合成需要首先研究多肽P3378与sCLU的相互作用位点，从而进行结构的优化，得到有效的多肽探针。第三，合成含BODIPY的多肽ZD2-1，研究其与纤维粘连蛋白的相互作用，结果表明此多肽可以与纤维粘连蛋白有很好的相互作用，通过荧光成像可用于前列腺癌的初步筛查。通过在这三类多肽的研究可以很好的证明基于BODIPY的β–转角模拟物的可行性和有效性，因此，将此技术模板化，推广运用到其它多肽–蛋白、蛋白–蛋白相互作用领域，为药研发提供信息。

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