Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology.
Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology.
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DOI：
10.3762/bjoc.8.233
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发表时间：
2012
影响因子：
2.7
通讯作者：
Faulstich H
中科院分区：
文献类型：
--
作者：
Anderl J;Echner H;Faulstich H
鬼笔毒素抑制细胞中微丝的动力学并导致细胞凋亡。由于细胞摄取差，这些作用不能在活细胞中研究，即使在毫摩尔毒素浓度下，鬼笔环肽也不能用于消除肿瘤细胞。通过将鬼笔毒素缀合至亲脂性或聚阳离子部分，如油酸、聚赖氨酸或Tat-肽，大大增强了摄取。这些缀合物对细胞具有致死毒性，小鼠成纤维细胞或Jurkat白血病细胞，在微摩尔范围内。细胞的摄取始于毒素缀合物与质膜的连接，随后是内吞作用，并且在大多数情况下，毒素从载体上裂解。有趣的是，鬼笔环肽进入细胞的内化率也显着增加的荧光部分四甲基罗丹明，以及高分子量甲氧基聚乙二醇，两种化合物迄今未知的摄取介导活性。结合载体的研究，在这项工作中将允许使用鬼笔毒素在实验细胞生物学和可能的肿瘤治疗。从鬼笔毒素中获得的发现也可以应用于鹅膏毒肽家族，例如，当α-鹅膏毒肽与油酸结合时，对细胞的毒性比天然毒素高100倍以上。这表明更普遍使用这里检查的部分来增强亲水性肽或药物进入活细胞的摄取的可能性。
Phallotoxins inhibit the dynamics of microfilaments in cells and lead to apoptosis. Due to poor cellular uptake these effects cannot be studied in live cells, even at millimolar toxin concentrations, nor can phalloidin be used for the elimination of tumor cells. Uptake is greatly enhanced by conjugation of phallotoxins to either lipophilic or polycationic moieties, such as oleic acid, polylysine, or Tat-peptide. These conjugates were lethally toxic for cells, e.g., mouse fibroblasts or Jurkat leukemia cells, in the micromolar range. Uptake into cells starts with the attachment of the toxin conjugates to the plasma membrane, followed by endocytosis and, in most cases, cleavage of the toxin from the carrier. Interestingly, the internalization rate of phalloidin into cells was also significantly increased by the fluorescent moiety tetramethylrhodaminyl, as well as by high molecular weight methoxy-polyethyleneglycol, two compounds unknown so far for their uptake-mediating activity. Conjugation to carriers as investigated in this work will allow the use of phallotoxins in experimental cell biology and possibly in tumor therapy. The findings obtained with phallotoxins could be applied also to the family of amatoxins, where α-amanitin, for example, when conjugated to oleic acid was more than 100-fold more toxic for cells than the native toxin. This suggests the possibility of a more general use of the moieties examined here to enhance the uptake of hydrophilic peptides, or drugs, into live cells.
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影响因子：
7.3
作者：
Heitz F;Morris MC;Divita G
通讯作者：
Divita G
影响因子：
10.3
作者：
Moldenhauer, Gerhard;Salnikov, Alexei V.;Faulstich, Heinz
通讯作者：
Faulstich, Heinz
影响因子：
10.8
作者：
Bradley, MO;Swindell, CS;Donehower, RC
通讯作者：
Donehower, RC
影响因子：
82.9
作者：
Rothbard, JB;Garlington, S;Khavari, PA
通讯作者：
Khavari, PA
影响因子：
7.8
作者：
ALLINQUANT, B;HANTRAYE, P;PROCHIANTZ, A
通讯作者：
PROCHIANTZ, A