光响应金属配合物催化的蛋白质/多肽的位点可控选择性水解

Site-selective cleavage of peptide bonds has been widely used in the preparation of functional peptides, peptide drugs and protein sequencing. Molecular machine is currently the frontier of research in both chemistry and nanotechnology. However, the application of light-driven molecular motor/molecular switches as light and heat regulated multi-state molecular switches into site-selective hydrolysis of protein / peptide is still very challenging and yet to be discovered. In our previous work, we have built up a smart catalyst based on light-driven molecular motor. Upon light irradiation and thermal relaxation, the helicity of the bisphosphine ligand changes and in turn opposite enantiomer can be produced in a palladium catalyzed reaction. Furthermore, we have developed a photoresponsive metal-helical complex (helicate) by attaching oligobipyridine strand to molecular motor. For the first time, the chirality of metal complex can be regulated by light. In this proposal, based on our previous work on chiral phosphine ligand and switchable helicate using molecular motor as the core structure, we plan to incorporate photo-responsive elements into the transition-metal complexes and construct photo-responsive catalyst with properties to target the hydrolysis of desired sites of peptide sequence. By introducing a light-switchable molecular switch into the metal complex, the configurations of catalyst will change under light irradiation and in turn the catalytic activity or the hydrolysis site of peptides will change. We expect to get light switch on/off systems or light-controlled highly site-selective catalysts. This is an important development of light responsive smart catalysts in biochemistry and has both theoretical and practical value.

肽键的选择性水解在功能性多肽的制备、多肽类药物的开发以及蛋白质测序等领域有着非常广泛的应用。分子机器是目前化学科学以及纳米科技的研究前沿，但是将光和热调控的分子马达/开关引入到对蛋白质/多肽的位点可控选择性水解研究还充满挑战。在之前的工作中，申请人成功地构建了基于分子马达的新型智能催化剂。在光的调控下，有机膦配体的手性可以发生翻转，进而催化反应产品的绝对构型发生了完全翻转。此外，申请者还将寡聚联吡啶接入到分子马达上，设计并实现了首例光控手性螺旋配合物。在以上工作基础上，本申请计划将光响应元件引入到具有肽键水解活性的金属配合物中，用于构建具有光响应特性的肽序列靶向水解催化剂；将研究光响应金属配合物在光照前后不同构型的异构体的催化水解活性以及位点选择性，以期得到光开关催化剂或者可控高序列选择性的催化剂。这是基于金属配合物的光控智能催化剂在生物化学领域的重要发展，具有显著的理论意义和现实价值。

蛋白/多肽的合成后修饰在自然界和合成中都有广泛应用。肽键的选择性水解在功能性多肽的制备、多肽类药物的开发以及蛋白质测序等领域有着非常广泛的应用。多肽中氨基酸的合成后修饰可有效改变肽类化合物的理化性质、增加水溶性、延长体内作用时间、改变其生物分布状况、消除免疫原性、降低毒副作用等。分子机器是目前化学科学以及纳米科技的研究前沿，但是将光和热调控的分子马达/开关引入到对蛋白质/多肽的位点可控选择性水解研究还充满挑战。在本项目中，光响应元件被成功引入到具有肽键水解活性的金属配合物中，用于构建具有光响应特性的肽序列靶向水解催化剂。我们还研究了脯氨酸残基的合成后修饰，成功实现了N-alpha位的选择性官能团化，该工作发表在了Nature Communications 并得到了广泛关注。在分子机器领域，我们设计的化学能驱动的分子马达研究成果发表了Chem。这些研究为继续研究多肽合成后修饰奠定了良好的基础，具有显著的理论意义和现实价值。

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