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首页> 外文期刊>Biochemistry >New Lytic Peptides Based on the D.L-Amphipathic Helix Motif Preferentially Kill Tumor Cells Compared to Normal Cells
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New Lytic Peptides Based on the D.L-Amphipathic Helix Motif Preferentially Kill Tumor Cells Compared to Normal Cells

机译：与正常细胞相比，基于D.L-Amphipathic Helix MOTIF的新的裂解肽优先杀死肿瘤细胞

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摘要

Despite significant advances in cancer therapy, there is an urgent need for drugs with a new mode of action that will preferentially kill cancer cells. Several cationic antimicrobial peptides, which bind strongly to negatively charged membranes, were shown to kill cancer cells slightly better than normal cells. This was explained by a slight increase (3-9%) in the level of the negatively charged membrane phosphatidylesrine (PS) in many cancer cells compared to their normal counterparts. Unfortunately, however, these peptides are inactivated by serum components. Here we synthesized and investigated the anticancer activity and the role of peptide charge, peptide structure, and phospholipid headgroup charge on the activity of a new group of diastereomeric lytic peptides (containing D- and L- forms of leucine and lysine; 15-17 amino acids long). The peptides are highly toxic to cancer cells, to a degree similar to or larger than that of mitomycin C. However, compared with mitomycin C and many native antimicrobial peptides, they are more selective for cancer cells. The peptides were investigated for (i) their binding to mono-and bilayer membranes by using the surface plasmon resonance (SPR) technique, (ii) their ability to permeate membranes by using fluorescence spectroscopy, (iii) their structure and their effect on the lipid order by using ATR-FTIR spectroscopy, and (iv) their ability to bind to cancer versus normal cells by using confocal microscopy. The data suggest that the peptides disintegrate the cell membrane in a detergent-like manner. However, in contrast to native antimicrobial peptides, the diastereomers bind and permeate similarly zwitterionic and PS-containing model membranes. Therefore, cell selectivity is probably determined mainly by improved electrostatic attraction of the peptides to acidic components on the surface of cancer cells (e.g. O-glycosylation of mucines). The simple composition of the diastereomeric peptides and their stability regarding enzymatic egradation by serum components make them excellent candidates for new chemotherapeutic drugs.
机译：尽管癌症治疗有重大进展，但迫切需要具有新的作用方式，优先杀死癌细胞。几种阳离子抗微生物肽，其强烈地与带负电的膜结合，被证明略微好于正常细胞略好杀死癌细胞。与其正常的对应物相比，在许多癌细胞中，在许多癌细胞中的带负电荷膜磷脂酰磷脂酰苯胺（PS）的水平略微增加（3-9％）解释。然而，遗憾的是，这些肽通过血清组分灭活。在这里，我们合成并研究了抗癌活性和肽电荷，肽结构和磷脂头组的作用对新的非对映体裂解肽的活性（含有D-和L-形式的亮氨酸和赖氨酸; 15-17个氨基酸长）。肽对癌细胞具有高毒性，与丝霉素C的程度类似或大于丝霉素C.然而，与丝霉素C和许多天然抗菌肽相比，它们对癌细胞更具选择性。通过使用表面等离子体共振（SPR）技术，（ii）通过使用荧光光谱（III）它们的结构及其对其的影响通过使用ATR-FTIR光谱，（IV）通过使用共聚焦显微镜，通过使用ATR-FTIR光谱和（iv）它们与正常细胞结合的能力。数据表明，肽以洗涤剂样方式崩解细胞膜。然而，与天然抗菌肽相反，非对映异构体结合和渗透的类似两性离子和含PS的模型膜。因此，可能主要通过改善肽对癌细胞表面上的酸性组分的静电组分（例如，粘膜的糖基化）来确定细胞选择性。血清组分的简单组合物的非对映异构肽及其关于酶促酶的稳定性，使其成为新化学治疗药物的优异候选者。

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  • 来源
    《Biochemistry》 |2003年第31期|共9页
  • 作者

    Niv Papo and Yechiel Shai;

  • 作者单位

    Department of Biological Chemistry The Weizmann Institute of Science Rehovot 76100 Israel;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物化学;
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