Design and Synthesis of Biocompatible, Hemocompatible, and Highly Selective Antimicrobial Cationic Peptidopolysaccharides via Click Chemistry
Design and Synthesis of Biocompatible, Hemocompatible, and Highly Selective Antimicrobial Cationic Peptidopolysaccharides via Click Chemistry
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通过点击化学设计和合成生物相容性、血液相容性和高选择性抗菌阳离子肽多糖
DOI：
10.1021/acs.biomac.9b00179
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发表时间：
2019-06-01
影响因子：
6.2
通讯作者：
Huang, Wei
中科院分区：
文献类型：
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作者：
Chen, Yun;Yu, Luofeng;Huang, Wei
阳离子抗菌肽及其合成类似物具有优良的抗菌活性，但其高毒性和低选择性阻碍了其生物医学应用。在这项研究中，我们报告了一系列的阳离子肽多糖合成的巯基-烯点击化学接枝抗菌多肽，甲基丙烯酸酯末端的聚（赖氨酸-随机-苯丙氨酸）（Me-KnFm），到巯基多糖（葡聚糖，地塞米松）的骨干。它们的共聚物（Dex-g-KnFm）对革兰氏阴性菌（铜绿假单胞菌和大肠杆菌）、革兰氏阳性菌（耐甲氧西林金黄色葡萄球菌（MRSA）和表皮葡萄球菌）和真菌（白色念珠菌）表现出有效的广谱抗菌和抗真菌活性，最小抑菌浓度范围为31.25-500 μ g.mL（-1）。更重要的是，Dex-g-KnFm共聚物不诱导MRSA的耐药性高达17代。此外，这些共聚物具有改善的血液相容性，并表现出良好的体外生物相容性与鼠成肌细胞（C2 C12）。在所合成的肽多糖中，Dex（L）-g-K12. 5 F12.5- 50%作为最佳试剂，其选择性是多肽分子最大值的200倍以上。此外，在小鼠细菌性脓毒症模型中获得了强的体内抗微生物功效，对数减少超过3。这些优良的生物学特性为Dex-g-KnFm在生物医学领域的应用提供了良好的前景。
Despite the excellent antimicrobial activity, the high toxicity and low selectivity of cationic antimicrobial peptides (AMPs) and their synthetic analogues impede their biomedical applications. In this study, we report a series of cationic peptidopolysaccharides synthesized by thiol-ene click chemistry of grafting antimicrobial polypeptides, methacrylate-ended poly(lysine-random-phenylalanine) (Me-KnFm), onto a thiolated polysaccharide (dextran, Dex) backbone. Their copolymers (Dex-g-KnFm) exhibit potent broad-spectrum antibacterial and antifungal activity against Gram-negative bacteria (Pseudomonas aeruginosa and Escherichia coli), Gram-positive bacteria [methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis], and fungi (Candida albicans) with minimal inhibitory concentrations in the range of 31.25-500 mu g.mL(-1). More importantly, Dex-g-KnFm copolymers did not induce drug resistance of MRSA up to 17 passages. In addition, these copolymers have an improved hemocompatibility and exhibit good in vitro biocompatibility with murine myoblast (C2C12) cells. Among the synthesized peptidopolysaccharides, Dex(L)-g-K12.5F12.5-50%, as the optimal agent, displayed a selectivity more than 200 times the maximum value of polypeptide molecules. Furthermore, a strong in vivo antimicrobial efficacy with a log reduction above 3 in a mouse bacterial sepsis model has been obtained. These excellent biological properties present a promising prospect for Dex-g-KnFm in biomedical applications.