基于β,γ-双氨基氨基酸的低毒耐酶解抗菌肽设计、合成及活性研究

Antimicrobial peptides (AMPs), a novel category of promising antibiotics, have attracted massive attention in recent years. Compared with traditional small molecular antibiotics, AMPs often have a broader antimicrobial spectrum and usually don’t induce bacterial resistance. Nevertheless, the systematic application of naturally occurring AMPs has been severely restricted by their high hemolytic activity and proteolytic sensitivity. Only a few methods have been conducted to reach new anti-infectives with optimized therapeutic index, among them, de novo designed AMPs based on unnatural amino acids seems rather promising. Unlike natural ones, these synthetic peptides often have stronger tendency to form stable conformations and are usually more resistant to peptidase or protease degradation. For these reasons, we plan to utilize β,γ-diamino acid as ‘dipeptide surrogate’ to reconstruct Gramicidin S, a well-known and historically important cyclic AMP with both strong antibacterial and hemolytic activity. Meanwhile, we will also use β,γ-diamino acid as building blocks to design helical AMPs with increased metabolic stability. Compared with more frequently used β- or γ-amino acids, another attractive feature of β,γ-diamino acid is the presence of additional un-amidated amino group enabling further functionalization. In fact, we have previously published several β,γ-diamino acid modified Gramicidin S analogues with absolutely diminished hemolytic activity while retained antibacterial activity. Collectively, this research combined the SARs of AMP and the advantages of physicochemical characteristics of β,γ-diamino acid, thus providing a potential path to access high activity, low cytotoxicity and proteolytic resistant AMPs.

抗菌肽是近年来极受关注的一类新型抗菌药物，相较于小分子抗生素，它们具有抗菌谱广且不易引起细菌耐药性等优点。然而，高溶血毒性与不耐酶解等限制抗菌肽系统性运用的问题却一直未得到有效解决。在有限的潜在解决方法中，基于非天然氨基酸设计抗菌肽是一种新兴却不失有效的策略，原因在于由其构建的多肽更易形成稳定的构象且代谢稳定性更强。基于此，本研究提出将β,γ-双氨基氨基酸模拟二肽“准同构”重构天然环抗菌肽Gramicidin S及以其作为结构单元设计螺旋抗菌肽的设想。相较于常用的β-或γ-氨基酸，β,γ-双氨基氨基酸兼具便于在其未成键氨基引入其他基团的优势。本研究前期结果显示，合理使用β,γ-双氨基氨基酸重构Gramicidin S关键区域可在保留其抗菌活性的同时，极大地降低溶血毒性。本课题充分结合了抗菌肽的构效关系和β,γ-双氨基氨基酸的理化结构特点，有望为获取高效、低毒且耐酶解抗菌肽提供一条新途径。

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