期刊
HELVETICA CHIMICA ACTA
卷 101, 期 10, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/hlca.201800112
关键词
guanidinium-rich peptides; biopolymer cyanophycin; dipeptide Adp (H-Asp-Arg-OH); fosmidomycin; glufosinate; herbicidal activity; in-vivo toxicity; cell penetration; confocal fluorescence microscopy (CFM)
资金
- European Research Council (ERC Consolidator Grant) [681587]
- NCCR Molecular Systems Engineering
- European Research Council (ERC) [681587] Funding Source: European Research Council (ERC)
Oligo-arginines are thoroughly studied cell-penetrating peptides (CPPs, Figures 1 and 2). Previous in-vitro investigations with the octaarginine salt of the phosphonate fosmidomycin (herbicide and anti-malaria drug) have shown a 40-fold parasitaemia inhibition with P.falciparum, compared to fosmidomycin alone (Figure3). We have now tested this salt, as well as the corresponding phosphinate salt of the herbicide glufosinate, for herbicidal activity with whole plants by spray application, hoping for increased activities, i.e. decreased doses. However, both salts showed low herbicidal activity, indicating poor foliar uptake (Table1). Another pronounced difference between in-vitro and in-vivo activity was demonstrated with various cell-penetrating octaarginine salts of fosmidomycin: intravenous injection to mice caused exitus of the animals within minutes, even at doses as low as 1.4mol/kg (Table2). The results show that use of CPPs for drug delivery, for instance to cancer cells and tissues, must be considered with due care. The biopolymer cyanophycin is a poly-aspartic acid containing argininylated side chains (Figure4); its building block is the dipeptide H-Asp-Arg-OH (H-Adp-OH). To test and compare the biological properties with those of octaarginines we synthesized Adp(8)-derivatives (Figure5). Intravenouse injection of H-Adp(8)-NH2 into the tail vein of mice with doses as high as 45mol/kg causes no symptoms whatsoever (Table3), but H-Adp(8)-NH2 is not cell penetrating (HEK293 and MCF-7 cells, Figure6). On the other hand, the fluorescently labeled octamers FAM-(Adp(OMe))(8)-NH2 and FAM-(Adp(NMe2))(8)-NH2 with ester and amide groups in the side chains exhibit mediocre to high cell-wall permeability (Figure6), and are toxic (Table3). Possible reasons for this behavior are discussed (Figure7) and corresponding NMR spectra are presented (Figure8).
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据