Noguchi Hirofumi, Matsumoto Shinichi
Diabetes Research Institute Kyoto, Kyoto 606-8507, Japan.
Acta Med Okayama. 2006 Feb;60(1):1-11. doi: 10.18926/AMO/30757.
The direct intracellular delivery of proteins has, until recently, been difficult to achieve, due primarily to the bioavailability barrier of the plasma membrane. During the past 15 years, a variety of peptides called protein transduction domains (PTDs) or cell penetrating peptides (CPPs), have been characterized for their ability to translocate into live cells. The most commonly studied are homeodomain transcription factors such as Antennapedia, the herpes simplex virus (HSV) type 1 protein VP22, and the human immunodeficiency virus (HIV-1) transactivator TAT protein. Recently, polyarginine exhibits even greater efficiency in terms of delivery of several peptides and proteins. Numerous examples of biologically active full-length proteins and peptides have been delivered to cells and tissues, both in vitro and in vivo. These studies offer new avenues for treatment of several diseases. The main mechanism of protein transduction is an electrostatic interaction with the plasma membrane, penetration into cells by macropinocytosis, and a release to cytoplasm and nuclei by retrograde transport. Moreover, the intercellular transfer of endogenous transcription factors, such as TAT and homeoproteins, seems to point to an original and important mode of signal transduction. The protein transduction systems have opened up several possibilities, not only for the development of new peptide/protein drugs but also for consideration of their physiological and developmental implications.
直到最近，由于质膜的生物利用度屏障，蛋白质的直接细胞内递送一直难以实现。在过去15年中，多种被称为蛋白质转导结构域（PTDs）或细胞穿透肽（CPPs）的肽，因其能够转运进入活细胞的能力而得到表征。研究最广泛的是同源域转录因子，如触角足蛋白，单纯疱疹病毒1型（HSV-1）蛋白VP22，以及人类免疫缺陷病毒（HIV-1）反式激活蛋白TAT。最近，就几种肽和蛋白质的递送而言，聚精氨酸表现出更高的效率。许多生物活性全长蛋白质和肽已在体外和体内被递送至细胞和组织。这些研究为多种疾病的治疗提供了新途径。蛋白质转导的主要机制是与质膜的静电相互作用，通过巨胞饮作用进入细胞，并通过逆行转运释放到细胞质和细胞核中。此外，内源性转录因子（如TAT和同源蛋白）的细胞间转移似乎指向一种原始且重要的信号转导模式。蛋白质转导系统不仅为新型肽/蛋白质药物的开发，也为考虑其生理和发育意义开辟了多种可能性。
