Novel pH-Sensitive Cyclic Peptides.
Novel pH-Sensitive Cyclic Peptides.
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DOI：
10.1038/srep31322
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发表时间：
2016-08-12
影响因子：
4.6
通讯作者：
Reshetnyak YK
中科院分区：
文献类型：
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作者：
Weerakkody D;Moshnikova A;El-Sayed NS;Adochite RC;Slaybaugh G;Golijanin J;Tiwari RK;Andreev OA;Parang K;Reshetnyak YK
合成了一系列含有色氨酸(W)和谷氨酸(E)残基的环肽，并评估了它们作为ph敏感剂靶向酸性组织和ph依赖的细胞质递送分子。生物物理研究揭示了多肽在高、低ph值时在细胞膜脂质双分子层内的作用和定位的分子机制。对称的环状肽c[(WE)4WC]和不对称的环状肽c[E4W5C]在脂质双分子层上转运类似大小的极性货物分子amanitin，并以pH和浓度依赖的方式诱导细胞死亡。荧光标记肽对小鼠酸性4T1乳腺肿瘤的靶向性进行了评价。在静脉给药后24小时，不对称环肽c[E4W5C]的肿瘤与肌肉比最高（5.6）。ph不敏感环肽c[R4W5C]，其中谷氨酸残基(E)被带正电的精氨酸残基(R)取代，没有表现出肿瘤靶向性。我们介绍了一类新的环状肽，它可以作为一种新的ph敏感工具，用于研究或靶向酸性组织。
A series of cyclic peptides containing a number of tryptophan (W) and glutamic acid (E) residues were synthesized and evaluated as pH-sensitive agents for targeting of acidic tissue and pH-dependent cytoplasmic delivery of molecules. Biophysical studies revealed the molecular mechanism of peptides action and localization within the lipid bilayer of the membrane at high and low pHs. The symmetric, c[(WE)4WC], and asymmetric, c[E4W5C], cyclic peptides translocated amanitin, a polar cargo molecule of similar size, across the lipid bilayer and induced cell death in a pH- and concentration-dependent manner. Fluorescently-labelled peptides were evaluated for targeting of acidic 4T1 mammary tumors in mice. The highest tumor to muscle ratio (5.6) was established for asymmetric cyclic peptide, c[E4W5C], at 24 hours after intravenous administration. pH-insensitive cyclic peptide c[R4W5C], where glutamic acid residues (E) were replaced by positively charged arginine residues (R), did not exhibit tumor targeting. We have introduced a novel class of cyclic peptides, which can be utilized as a new pH-sensitive tool in investigation or targeting of acidic tissue.