基于抗菌肽OH-CATH30设计与合成新型阳离子桥联订书针肽类似物

Antimicrobial peptides are one of the important classes of endogenous biological peptides. Except their direct antibacterial activity, antimicrobial peptides also have significant immunomodulatory activity as effector molecules in the innate immune system. Considering the protease susceptibility and moderate antibacterial activity of antimicrobial peptides, in this project, we will introduce a macrocyclic moiety into antimicrobial peptide with the aim to stabilize the α-helix of antimicrobial peptide and expect to obtain antimicrobial peptide mimics with protease resistance and great biological activity. Crosslinking the peptide sidechain to form staple peptide is an excellent way to stabilize the α-helix of peptide, and has been known as a great way to enhance the biological activity and selectivity of peptides. But there are limited macrocyclization protocols to introduce a staple structure into antimicrobial peptide on the hydrophilic surface. Therefore, employing the monoalkylating reaction of amino group of the lysine sidechain, novel cation-bridged macrocycle is designed as staple to keep the cationic characteristics of the hydrophilic surface of antimicrobial peptides. Meanwhile, by systematic investigation of the effects of the introduction of staple structure on both the hydrophilic and hydrophobic surface of antimicrobial peptide, it is our expectation to obtain the structure-activity relationships between the peptide secondary structure and antibacterial activity. And it will also provide a substantial experimental data for further understanding the molecular mechanism of antimicrobial peptide. The choosing of antimicrobial peptide OH-CATH30 with immunomodulatory activity as model peptide in this project is the first exploration of the application of stapled antimicrobial peptide mimics in immune modulation area, which will be of great interesting and of significant. All of the above will provide us a great foundation for the further development of new antibacterial pharmaceuticals based on antimicrobial peptides.

抗菌肽是一类具有重要生理作用的内源性多肽，除了直接的杀菌作用外，还具有重要的免疫调节作用。针对抗菌肽蛋白酶稳定性差和抗菌活性低的缺点，本项目希望通过引入大环化结构，稳定抗菌肽的alpha-螺旋结构，获得具有抗蛋白酶水解和良好生理活性的抗菌肽类似物。现有的有限的大环化方法无法在抗菌肽的亲水性表面引入订书针结构，因此，本项目将通过赖氨酸侧链的氨基的单烷基化反应发展新型的阳离子桥联大环，在引入订书针结构的同时，保持抗菌肽亲水性表面的阳离子特征。通过系统性研究在抗菌肽亲水性表面和疏水性表面引入订书针结构的影响，以期得到抗菌肽的二级结构与其抗菌活性之间的构效关系，并对抗菌肽的分子作用机制研究提供更多实验依据。利用具有免疫调控活性的抗菌肽OH-CATH30为模版，将为抗菌肽订书针肽类似物在免疫调控领域的应用做出探索性的研究。基于上述研究，本项目将为进一步开发以抗菌肽为基础的新型抗菌药物奠定重要基础。

抗菌肽是一类具有重要生理作用的内源性多肽，除了直接的杀菌作用外，还具有重要的免疫调节作用。针对抗菌肽蛋白酶稳定性差和抗菌活性低的缺点，本项目希望通过引入大环化结构，稳定抗菌肽的alpha-螺旋结构，获得具有抗蛋白酶水解和良好生理活性的抗菌肽类似物。本项目成功发展了一种利用Mistunobu反应作为关键步骤的新型大环多肽合成方法，首次实现了在抗菌肽亲水性表面引入订书针结构，并合成了一系列基于OH-CATH30抗菌肽为基础的环状抗菌肽的合成，并进行了抗菌活性筛选。利用烯烃复分解反应合成了一系列OH-CATH30为基础，在疏水性表面引入订书针结构的环状抗菌肽，并进行了抗菌活性筛选。同时，成功实现了具有双订书针结构环状抗菌肽的合成，在抗菌肽亲水及疏水表面实现了订书针结构的引入，对所合成的双环抗菌肽进行了抗菌活性筛选。基于上述合成的大环化抗菌肽类似物库，初步研究了在抗菌肽亲水性表面和疏水性表面引入订书针结构对抗菌肽生理活性的影响。另外，对筛选出的具有良好抗菌活性的前体化合物，初步探索了其在免疫调节中的应用，研究了其对巨噬细胞炎症因子的调节。通过设计、合成及研究环状抗菌肽的生理活性，本课题筛选出了一些具有良好生理活性的前体化合物，为后续发展新型的抗生素奠定了重要基础，证明了抗菌肽是新型抗生素开发的重要来源，具有广泛的应用前景。

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