抗菌肽及类抗菌肽的设计、合成及性能研究

Antibiotics are widely used and abused in clinic because its significant antimicrobial effect, which result in lots of bacteria to develop resistance to them. Design and synthesis new antibacterial drugs is one of most urgent task for scientist. Antimicrobial peptides are important candidate to solve this problem. Natural antimicrobial peptides (AMP) have excellent antibacterial ability, and at same time, bacteria are difficult have resistance to them due to AMP have different antibacterial mechanism from traditional antibiotics. However, the separation and purification of natural antimicrobial peptides is difficult and costly. Therefore, scientists design and synthesis different kind of AMP by chemical method. However, up to now, the relationship between the structure and antibacterial ability of AMP is still unclearly. But they have concluded that AMP must contain two components: positive charge amino acid and hydrophobic amino acid. According to the antibacterial mechanism of natural antimicrobial peptides, we design three series of AMP or mimetic AMP copolymers: 1. amphiphilic block copolypeptides. 2.alternating mimetic antibacterial peptide copolymers, 3.PCL was used to replace hydrophobic amino acid to combine with polylysine to prepare PCL-Polylysine block mimetic antibacterial peptide copolymers.

抗生素因抗菌效果显著得以在临床上广泛应用乃至滥用，致使大量细菌对其产生耐药性。研发新型的抗菌药物是目前世界上最紧迫的课题之一。抗菌肽是解决这一问题的最佳候选者。天然抗菌肽具有很好的抗菌性能，同时由于其不同于传统抗生素的抗菌机理，使病菌对其难以产生耐药性。但由于天然抗菌肽的提纯和分离较困难，而且成本高。因此，抗菌肽研究者设计并用化学合成法合成了各种结构的抗菌肽，但到目前为止，研究者还未完全弄清楚抗菌肽的结构与抗菌性能的关系，但抗菌肽必须含有两个要素(含有带正电荷的氨基酸，疏水的氨基酸残基)已达成共识。我们依据天然抗菌肽的抗菌机理，通过三种策略构筑抗菌肽及类肽共聚物：1.两亲性嵌段聚多肽，2.类抗菌肽交替共聚物，3.用己内酯或聚己内酯代替抗菌肽中的疏水氨基酸制备各种类抗菌肽。通过这些系列的抗菌肽及类抗菌肽，研究其结构、组成与性能的关系，找到设计、合成高效抗菌肽的普适性规律。

抗生物因其抗菌效果优异得以在临床上广泛应用甚至滥用，从而产生大量的耐药菌。开发新型的抗生素是目前我们所面临的最重要的课题之一。科学家们发现抗菌肽是解决细菌耐药性的最佳候选者。天然抗菌肽具有广谱抗菌、抗菌活性高等特点。更重要的是，其抗菌机理不同于传统抗生素，这使得细菌对其难以产生耐药性。但由于天然抗菌肽的提纯、分离较困难，且成本高，这限制了其在临床的应用。我们设计合成了四个系列的类抗菌肽：1.通过分子设计，选择不同的疏水氨基酸，利用NCA开环聚合法合成各种两亲性嵌段多肽. 2. 利用疏水的有机小分子替代抗菌太重疏水氨基酸的组分. 3. 用固相合成法合成了两亲性三嵌段短肽。4. 用聚酯结构的链段替代疏水氨基酸制备类抗菌肽，研究其结构、组成与类肽聚合物的抗菌性能的关系，同时考察聚酯结构对其生物相容性的影响。本工作突破了抗菌肽原有的设计思路，不拘泥于抗菌肽的一级序列结构，而是模拟天然抗菌肽抗菌的最主要的两个因素：一，具有正电荷；二，具有疏水氨基酸。成功地用有机疏水小分子或高分子链段替代抗菌肽中的疏水氨基酸合成出多种抗菌肽或类抗菌肽，为抗菌肽的设计、合成初步探索了方向。