酶激活聚氨基酸类抗菌高分子的合成及构效关系研究

With the wide use of antibiotics, more and more antibiotic-resistant bacteria emerged, which has become one of the biggest threats to global health. Thus, the development of new classes of antibiotics is urgently needed to address this challenge. It is well-documented that cationic antibacterial peptides pose broad-spectrum and highly effective antibacterial activities in many organisms with low propensity for resistance development, which might form the foundation for a new and promising class of antibiotic. However, the relatively high cost, limited stability and unknown toxicology have given a set of obstacles to the clinical translation of antibacterial peptides. To address this issue, we propose to synthesize a series of cationic polypeptides with structural mimic to natural antibacterial peptides via combination of ring-opening polymerization and “click” side-chain modification. Then, the antibacterial activities and possible antibacterial mechanism of the resultant cationic polypeptides will be thoroughly investigated in correlation with their different hydrophilic-hydrophobic ratios, different structures of hydrophobic chains and hydrophilic amino groups. Furthermore, the amino groups will be “shielded” by an enzyme-cleavable PEG chain to improve the stability of the synthetic antibacterial polypeptides in blood circulation. The obtained “PEG-shielded” antibacterial polypeptides can be activated by microbe-associated enzymes through enzyme-induced deshielding of amino groups in the side chains. Based on the careful design of the PEG-shielding (the chemical structure of enzyme-cleavable site, the length of PEG chain and the grafting density of shielding PEG), various antibacterial polypeptides with advantages of low-cost, highly enzyme-activatable antibacterial activities, excellent stability and biocompatibility would be obtained, which may spawn a new generation of antibiotics with a broad range of topical and systemic applications against infections.

随着抗生素的广泛使用，耐药菌不断涌现，已成为人类健康的最大威胁之一。因此，研发新型高效的抗菌药物是眼下保障健康的当务之急。研究表明，天然存在的阳离子抗菌肽具有广谱、高效的杀菌效果，且不易产生耐药性，是一种极具前景的新型抗菌药物；然而，其高昂的价格、较低的稳定性以及未知的毒理，严重阻碍了该类抗菌肽的临床转化。为此，本项目拟从模拟天然抗菌肽结构出发，通过开环聚合结合“click”反应进行侧基修饰的方法，制备一系列具有稳定二级结构，不同亲疏水比例，以及不同疏水侧基和阳离子结构的抗菌聚氨基酸材料；并通过抑菌实验，筛选具有良好抗菌效果的阳离子抗菌材料及其基本结构特征，探究其抑菌机制。进一步，利用含酶激活位点的PEG对上述抗菌高分子的胺基侧基进行修饰，通过调控酶激活位点化学结构、PEG链长及其接枝密度，获得一系列价格低廉，且具有高效酶激活抑菌功能，以及良好血液稳定性和生物相容性的新型抗菌聚氨基酸材料。

随着抗生素的广泛使用，耐药菌不断涌现，已成为人类健康的最大威胁之一。因此，研发高效的抗菌药物是面向人民生命健康的主要任务之一。然而，目前抗生素的研发大大落后于耐药菌的发展，耐药菌感染的治疗面临严峻挑战。抗菌高分子材料具有独特的膜裂解杀菌效应，能够有效杀死细菌，并抑制耐药菌进展，有望成为新一代的杀菌药物。然而，传统的抗菌高分子材料往往具有较高的毒副作用，难以获得广泛的临床应用。为此，本项目从模拟天然抗菌肽结构出发，制备一系列酶响应抗菌氨基酸材料，并对其构效关系进行系统研究，期望获得高效安全的新型抗菌高分子材料。具体研究成果如下：（1）设计、制备了一系列阳离子聚氨基酸材料，研究发现通过调控阳离子聚氨基酸聚合度和端基疏水基团，我们可以获得兼具高杀菌能力和低溶血性能的酶响应聚氨基酸材料；（2）将抗菌聚氨基酸材料与水凝胶结合，制备了系列具有抗菌性能的水凝胶敷料，可用于治疗感染性创面；（3）尝试将抗菌治疗理念拓展到抗肿瘤领域，提出了将具有膜裂解作用的聚氨基酸材料用作抗肿瘤药物的新理念，为难治性肿瘤的治疗提供一种新思路。综上，在本项目的资助下，我们设计开发多种新型聚氨基酸材料，实现了高效的抗菌治疗和抗肿瘤治疗，为应对耐药菌引发的感染疾病提供一个有前景的材料平台。本项目顺利完成了预期的研究任务，并发表学术论文14篇，申请中国发明专利5项，其中已授权3项。