Arginine-rich molecular transporters for drug delivery: Role of backbone spacing in cellular uptake
Arginine-rich molecular transporters for drug delivery: Role of backbone spacing in cellular uptake
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DOI：
10.1021/jm0105676
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发表时间：
2002-08-15
影响因子：
7.3
通讯作者：
Wender, PA
中科院分区：
文献类型：
--
作者：
Rothbard, JB;Kreider, E;Wender, PA
精氨酸的短低聚物，无论是单独的还是与治疗剂或大的生物聚合物结合时，已被证明可以很容易地跨越各种生物屏障（例如，脂质双分子层和上皮组织）。分子模型表明，只有这些转运蛋白的侧链胍基的一个子集可能需要与共同表面（如质膜或细胞表面受体）接触的运输。为了评估这一假设，我们制备了一系列包含7个精氨酸和3个非精氨酸残基的十聚体。在进入细胞的能力方面，这些混合十聚体中的一些与全精氨酸十聚体相当。更重要的是，这些含有7个精氨酸的十聚体几乎无一例外地比七精氨酸本身表现得更好，这表明残基之间的间距对运输也很重要。通过一个包含七个精氨酸的低聚物文库，更充分地评估了间距的影响，这些精氨酸由一个或多个非连续的非α氨基酸分开。该研究鉴定了一系列新的高效分子转运体。
Short oligomers of arginine, either alone or when conjugated to therapeutic agents or large biopolymers, have been shown to cross readily a variety of biological barriers (e.g., lipid bilayers and epithelial tissue). Molecular modeling suggests that only a subset of the side chain guanidinium groups of these transporters might be required for transport involving contact with a common surface such as a plasma membrane or cell surface receptor. To evaluate this hypothesis, a series of decamers were prepared that incorporated seven arginines and three nonarginine residues. Several of these mixed decamers were comparable to the all arginine decamer in their ability to enter cells. More significantly, these decamers containing seven arginines performed almost without exception better than heptaarginine itself, suggesting that spacing between residues is also important for transport. The influence of spacing was more fully evaluated with a library of oligomers incorporating seven arginines separated by one or more nonconsecutive, non-alpha-amino acids. This study led to the identification of a new series of highly efficient molecular transporters.