具有不同结构特征的抗菌肽的协同效应和构效关系研究

发布时间：2018-05-19 16:54

  本文选题：抗菌肽 + 协同活性　； 参考：《兰州大学》2011年硕士论文

【摘要】：迄今为止,一些抗菌肽已经进入临床试验,并展示出高效的抗肿瘤,抗革兰氏阳性菌,阴性菌和真菌的活性。但是还存在许多缺陷影响抗菌肽的应用,首先大多数抗菌肽主要用于局部治疗,很少用于全身系统性使用,主要原因是其活性可能会被复杂的体液如血浆,血清,唾液和痰液所抑制；其次抗菌肽在体内治疗指数较低以及由于蛋白酶消化和肾脏快速清除作用具有较短的半衰期,一定的毒副作用,因而设计出具有较强抗肿瘤活性和较低溶血活性的稳定的抗菌肽是我们的目标。 为了研究Leu, Lys,Ahx尤其是Pro残基对于协同活性和抗肿瘤活性的影响,我们通过使用Leu, Lys, Ahx和Pro残基作为连接子,将MP与Anoplin连接起来形成新的具有25个氨基酸残基的5条抗菌肽(AM-1, AM-2, AM-3, AM-4和AM-5),它们在疏水性,两亲性,α-螺旋成分的含量,空间伸展性和电荷上不同,便于筛选出具有较强抗肿瘤活性和较低溶血活性的目标抗菌肽。它们的序列如下：MP:Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2 Anoplin:Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-NH2 AM-1:Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-Lys-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2 AM-2:Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-Pro-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2 AM-3:Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-Ahx-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2 AM-4:Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-Pro-Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-NH2 AM-5:Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-Leu-Ile-Asn-Leu-Lys-Ala-Leu-Ala-Ala-Leu-Ala-Lys-Lys-Ile-Leu-NH2 实验结果表明,相对于母体MP和Anoplin, AM系列5条肽的体外抗肿瘤活性明显增强了,表现为对HEPG-2细胞,Hela细胞和MDA细胞的IC50值明显低于母体,增加了协同效应；同时也具有一定的选择性毒性,对正常细胞(NIH-3T3)的杀伤作用低于母体；在溶血方面,5条肽的溶血活性都比母体要强,这可能与Pro的引入,电荷和疏水性的增加有关；与AM-5相比AM-2具有较强的抗肿瘤活性和较低的溶血活性,因而在肽链中心引入Pro可能是增加抗肿瘤活性,增强药物选择性和协同效应的一个很好的策略。 对于如何平衡抗菌肽抗肿瘤活性和选择性毒性这一对关系,目前我们还没有弄清楚。虽然部分AM系列抗菌肽在溶血活性和细胞选择性上不尽人意,但是作为成功与失败的的例子,为今后我们能设计出更好的目标抗菌肽提供了宝贵的经验。
[Abstract]:To date, some antimicrobial peptides have entered clinical trials and have shown highly potent antitumor, anti-gram-positive, negative and fungal activities. But there are still many defects affecting the application of antimicrobial peptides. First, most antimicrobial peptides are mainly used in local therapy, but rarely in systemic use, mainly because their activity may be complicated by body fluids such as plasma, serum, Saliva and sputum were inhibited; secondly, antimicrobial peptides had a lower therapeutic index in vivo and a shorter half-life due to protease digestion and rapid renal clearance, with certain toxic and side effects. Therefore, it is our goal to design stable antimicrobial peptides with strong anti-tumor activity and low hemolytic activity. To study the effects of Leu, Lysn Ahx, especially Pro residues, on synergistic and antitumor activities, we used Leu, Lys, Ahx and Pro residues as connectors. MP was connected with Anoplin to form five new antimicrobial peptides with 25 amino acid residues: AM-1, AM-2, AM-3, AM-4 and AM-5, which were different in hydrophobicity, amphiphilicity, 伪 -helix content, spatial extensibility and charge. Objective antimicrobial peptides with strong anti-tumor activity and low hemolytic activity are easy to be screened. 瀹冧滑鐨勫簭鍒楀�備福�

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