本文選題：抗菌肽 + 協(xié)同活性�。� 參考：《蘭州大學》2011年碩士論文

【摘要】：迄今為止,一些抗菌肽已經(jīng)進入臨床試驗,并展示出高效的抗腫瘤,抗革蘭氏陽性菌,陰性菌和真菌的活性。但是還存在許多缺陷影響抗菌肽的應用,首先大多數(shù)抗菌肽主要用于局部治療,很少用于全身系統(tǒng)性使用,主要原因是其活性可能會被復雜的體液如血漿,血清,唾液和痰液所抑制；其次抗菌肽在體內(nèi)治療指數(shù)較低以及由于蛋白酶消化和腎臟快速清除作用具有較短的半衰期,一定的毒副作用,因而設(shè)計出具有較強抗腫瘤活性和較低溶血活性的穩(wěn)定的抗菌肽是我們的目標。 為了研究Leu, Lys,Ahx尤其是Pro殘基對于協(xié)同活性和抗腫瘤活性的影響,我們通過使用Leu, Lys, Ahx和Pro殘基作為連接子,將MP與Anoplin連接起來形成新的具有25個氨基酸殘基的5條抗菌肽(AM-1, AM-2, AM-3, AM-4和AM-5),它們在疏水性,兩親性,α-螺旋成分的含量,空間伸展性和電荷上不同,便于篩選出具有較強抗腫瘤活性和較低溶血活性的目標抗菌肽。它們的序列如下：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 實驗結(jié)果表明,相對于母體MP和Anoplin, AM系列5條肽的體外抗腫瘤活性明顯增強了,表現(xiàn)為對HEPG-2細胞,Hela細胞和MDA細胞的IC50值明顯低于母體,增加了協(xié)同效應；同時也具有一定的選擇性毒性,對正常細胞(NIH-3T3)的殺傷作用低于母體；在溶血方面,5條肽的溶血活性都比母體要強,這可能與Pro的引入,電荷和疏水性的增加有關(guān)；與AM-5相比AM-2具有較強的抗腫瘤活性和較低的溶血活性,因而在肽鏈中心引入Pro可能是增加抗腫瘤活性,增強藥物選擇性和協(xié)同效應的一個很好的策略。 對于如何平衡抗菌肽抗腫瘤活性和選擇性毒性這一對關(guān)系,目前我們還沒有弄清楚。雖然部分AM系列抗菌肽在溶血活性和細胞選擇性上不盡人意,但是作為成功與失敗的的例子,為今后我們能設(shè)計出更好的目標抗菌肽提供了寶貴的經(jīng)驗。
[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, 偽 -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涓，

本文編號：1910906