具有高效抗真菌活性的β-氨基酸聚合物  

β-Amino Acid Polymers Displaying Potent Antifungal Activity

作　　者：万江林 张东辉 周敏 刘润辉[1,2] WAN Jianglin;ZHANG Donghui;ZHOU Min;LIU Runhui(State Key Laboratory of Bioreactor Engineering,East China University of Science and Technology,Shanghai 200237,China;Key Laboratory for Ultrafine Materials of Ministry of Education,Research Center for Biomedical Materials of Ministry of Education,School of Materials Science and Engineering,East China University of Science and Technology,Shanghai 200237,China;School of Biotechnology,East China University of Science and Technology,Shanghai 200237,China;School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China)

机构地区：[1]华东理工大学生物反应器工程国家重点实验室,上海200237 [2]华东理工大学材料科学与工程学院超细材料制备与应用教育部重点实验室,教育部医用生物材料工程研究中心,上海200237 [3]华东理工大学生物工程学院,上海200237 [4]华东理工大学药学院,上海200237

出　　处：《功能高分子学报》2023年第5期468-475,共8页Journal of Functional Polymers

基　　金：国家自然科学基金(22075078,22205063);上海市优秀学术带头人(20XD1421400);上海市启明星培育扬帆专项(22YF1410100)。

摘　　要：通过模拟带有正电荷和两亲性结构的天然宿主防御肽(HDPs),采用β-氨基酸N-硫代羧基酸酐(β-NTA)开环聚合方法,将不同比例正电荷单体N(α)-Z-DL-2,3-二氨基丙酸N-硫代羧基酸酐(DAP)和疏水性单体3-氨基-2-(苯基)丙酸N-硫代羧基酸酐(Ph)进行共聚,得到了系列两亲性β-氨基酸聚合物(DAPxPhy)20。通过核磁共振氢谱仪(1H-NMR)和凝胶渗透色谱仪(GPC)对其链长和结构进行表征。结果表明:(DAPxPhy)20聚合物具有高抗白色念珠菌活性,最低抑菌浓度(MIC)为1.56~12.5μg/mL,且该聚合物在200μg/mL质量浓度下未对人血红细胞和成纤维细胞造成明显毒性。Invasive fungal infections are spreading around the world,causing over 1.5 million deaths worldwide each year.Potent antifungal agents with low toxicity are urgently needed due to the limited antifungal drugs available.Host defense peptides(HDPs)demonstrated potent activity against microorganisms because of their broad-spectrum antimicrobial activity and insusceptibility to antimicrobial resistance.However,the wide application of HDPs is hindered by their inherent shortcomings such as difficult synthesis,expensiveness and poor proteolytic stability.To resolve these problems,a series ofβ-amino acid polymers(DAPxPhy)20 were designed and synthesized by mimicking the structure of HDPs.The random copolymers were obtained by controllable and water insensitive ring-opening polymerization ofβ-amino acid N-thiocarboxyanhydrides(β-NTA)with N(α)-Z-DL-2,3-diaminopropionic acid N-thiocarboxyanhydrides(DAP)as the cationic monomer and 3-amino-2-(phenyl)propionic acid N-thiocarboxyanhydrides(Ph)as the hydrophobic monomer.The chain length and structure of polymers were characterized by 1H-NMR and gel penetration chromatography(GPC).Results showed that(DAPxPhy)20 had potent antifungal activity to C.albicans K1 with minimum inhibitory concentration(MIC)at 1.56—12.5μg/mL.The antifungal activity weakened with the increasing of Ph content,since the reduction of the positive charge ratio might lead to a weakened electrostatic interaction with the fungal cell membrane.Theseβ-amino acid polymers did not cause significant hemolysis of human red blood cells at the mass concentration of 400μg/mL and also exhibited low cytotoxicity upon NIH 3T3 fibroblast cells at 200μg/mL.This study demonstrated that(DAPxPhy)20 exhibited potent antifungal activity with low hemolysis,cytotoxicity and easy preparation,showing broad potential in the treatment of fungal infections.

关 键 词：β-氨基酸聚合物 β-NTA开环聚合 两亲性聚合物 高抗真菌活性 低毒性 

分 类 号：R318.08[医药卫生—生物医学工程]