Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity.
Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity.
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DOI：
10.3390/molecules22111929
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发表时间：
2017-11-08
期刊：
影响因子：
--
通讯作者：
Giralt E
中科院分区：
文献类型：
--
作者：
Kalafatovic D;Giralt E
有效的细胞内药物传递和靶标特异性常常受到生物屏障存在的阻碍。因此，有效穿越细胞膜的化合物是提高非渗透性药物治疗价值和靶向特异性的关键。细胞穿透肽（CPPs）的发现和通过模仿病毒使用的自然穿透结构域的早期设计方法提高了细胞内递送的效率。在这些受自然启发的例子之后，已经开发了许多合理设计的CPPs。在这篇综述中，各种CPP设计将被描述，包括线性和柔性的，带正电的，通常是两亲性的CPP，以及更刚性的版本，包括环状的，钉接的，或二聚体和/或多价的，自组装的肽或肽模拟物。将不同的设计策略应用于已知的CPPs物理化学性质，为提高其渗透效率和/或内化动力学提供了机会。这导致新CPP的设计复杂性增加，但并不总是导致更大的CPP活动。因此，CPPs向临床环境的转变仍然是一个挑战，因为在体外研究中使用的各种内化途径和细胞的异质性同时存在。
Efficient intracellular drug delivery and target specificity are often hampered by the presence of biological barriers. Thus, compounds that efficiently cross cell membranes are the key to improving the therapeutic value and on-target specificity of non-permeable drugs. The discovery of cell-penetrating peptides (CPPs) and the early design approaches through mimicking the natural penetration domains used by viruses have led to greater efficiency of intracellular delivery. Following these nature-inspired examples, a number of rationally designed CPPs has been developed. In this review, a variety of CPP designs will be described, including linear and flexible, positively charged and often amphipathic CPPs, and more rigid versions comprising cyclic, stapled, or dimeric and/or multivalent, self-assembled peptides or peptido-mimetics. The application of distinct design strategies to known physico-chemical properties of CPPs offers the opportunity to improve their penetration efficiency and/or internalization kinetics. This led to increased design complexity of new CPPs that does not always result in greater CPP activity. Therefore, the transition of CPPs to a clinical setting remains a challenge also due to the concomitant involvement of various internalization routes and heterogeneity of cells used in the in vitro studies.
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