Efficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo.
Efficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo.
复制标题
多功能嵌合肽在体内外对蛋白质的有效胞内递送。
DOI：
10.1038/s41467-021-25448-z
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发表时间：
2021-08-26
影响因子：
16.6
通讯作者：
Xia N
中科院分区：
文献类型：
--
作者：
Yu S;Yang H;Li T;Pan H;Ren S;Luo G;Jiang J;Yu L;Chen B;Zhang Y;Wang S;Tian R;Zhang T;Zhang S;Chen Y;Yuan Q;Ge S;Zhang J;Xia N
细胞穿透肽的蛋白质递送为细胞内靶标的治疗或生物应用开辟了可能性；然而，细胞穿透肽介导的蛋白质递送通常存在内体逃逸无效和血清耐受性低的问题，从而限制了体内疗效。在这里，我们提出了一个由四个模块组成的细胞内蛋白质递送系统：细胞穿透肽，ph依赖性膜活性肽，内体特异性蛋白酶位点和亮氨酸拉链。该系统表现出更高的递送效率和血清耐受性，这取决于蛋白水解裂解促进的内体逃逸和亮氨酸拉链为基础的二聚化。在小鼠模型中，静脉注射融合了该系统的蛋白磷酸酶1B成功地抑制了肿瘤坏死因子-α-诱导的全身炎症反应和对乙酰氨基酚诱导的急性肝衰竭。我们认为，使用多功能嵌合肽的策略对于开发细胞穿透肽为基础的蛋白质递送系统具有重要价值，并有助于开发针对细胞内靶点的生物大分子药物。细胞穿透肽的蛋白质递送存在内体逃逸无效和血清耐受性低的问题，因此限制了治疗的成功。在这里，作者提出了一个细胞内蛋白质递送系统，并在体外证明了有效的递送和体内肝衰竭模型的治疗效果。
Protein delivery with cell-penetrating peptide is opening up the possibility of using targets inside cells for therapeutic or biological applications; however, cell-penetrating peptide-mediated protein delivery commonly suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting in vivo efficacy. Here, we present an intracellular protein delivery system consisting of four modules in series: cell-penetrating peptide, pH-dependent membrane active peptide, endosome-specific protease sites and a leucine zipper. This system exhibits enhanced delivery efficiency and serum tolerance, depending on proteolytic cleavage-facilitated endosomal escape and leucine zipper-based dimerisation. Intravenous injection of protein phosphatase 1B fused with this system successfully suppresses the tumour necrosis factor-α-induced systemic inflammatory response and acetaminophen-induced acute liver failure in a mouse model. We believe that the strategy of using multifunctional chimaeric peptides is valuable for the development of cell-penetrating peptide-based protein delivery systems, and facilitate the development of biological macromolecular drugs for use against intracellular targets. Protein delivery with cell-penetrating peptides suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting treatment success. Here the authors present an intracellular protein delivery system and demonstrate efficient delivery in vitro and therapeutic efficacy in a liver failure model in vivo.
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影响因子：
5
作者：
Diederich S;Dietzel E;Maisner A
通讯作者：
Maisner A
DOI：
10.3390/ph5111177
发表时间：
2012-11-01
期刊：
Pharmaceuticals (Basel, Switzerland)
影响因子：
--
作者：
Erazo-Oliveras A;Muthukrishnan N;Baker R;Wang TY;Pellois JP
通讯作者：
Pellois JP
影响因子：
4.6
作者：
Cai, SR;Xu, G;McLeod, HL
通讯作者：
McLeod, HL
影响因子：
5.1
作者：
Bunchorntavakul, Chalermrat;Reddy, K. Rajender
通讯作者：
Reddy, K. Rajender
影响因子：
46.9
作者：
Cabantous, S;Terwilliger, TC;Waldo, GS
通讯作者：
Waldo, GS