Endosomal escape is a rate-limiting step in the cytosolic delivery of therapeutic drugs. Overcoming this barrier is crucial to achieve an effective biological based therapy. In this work, we evaluated the ability of a synthetic biomimetic peptide derived from the GALA to facilitate endosomal escape of protein drugs. Our results showed that the cytoplasmic distribution of GALA fusion proteins changed according to the hydrophobicity of GALA. One of the synthetic peptides, GALA3, significantly enhanced the endosomal escape efficiency of protein drugs. The cytosolic delivery capacity of GALA3 was significantly higher than that of several previously reported endosomal escape peptides, including hemagglutinin 2 (HA2). Moreover, when GALA3 was fused to BLF1-HBP, a ribosome-inactivating protein with cell-penetrating peptide HBP, the cytotoxicity of the fusion protein was significantly increased in various cell lines, including H460, HeLa, A549, and SMCC-7721. The growth inhibition effect of GALA3-BLF1-HBP was at least 20 times greater than that of BLF1-HBP alone in different tumor cell lines. GALA3 effectively promoted the endosomal escape of BLF1-HBP in a pH-dependent manner and greatly enhanced the apoptotic activity of BLF1-HBP. Taken together, our data show that by adjusting the hydrophobicity of GALA we obtained a more effective endosomal escape peptide. Therefore, GALA3-fusions can improve the efficiency of therapeutic protein drugs.

中文翻译：

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通过GALA3（一种疏水性降低的内体逃逸肽）有效地治疗药物。

内体逸出是治疗药物的胞质递送中的限速步骤。克服这一障碍对于实现有效的基于生物学的治疗至关重要。在这项工作中，我们评估了衍生自GALA的合成仿生肽促进内体蛋白药物逸出的能力。我们的结果表明GALA融合蛋白的细胞质分布根据GALA的疏水性而改变。一种合成肽GALA3显着提高了蛋白质药物的内体逃逸效率。GALA3的胞质传递能力明显高于先前报道的几种内体逃逸肽，包括血凝素2（HA2）。此外，当GALA3与BLF1-HBP融合时，核糖体失活蛋白与细胞穿透肽HBP融合，融合蛋白的细胞毒性在包括H460，HeLa，A549和SMCC-7721在内的各种细胞系中均显着增加。在不同肿瘤细胞系中，GALA3-BLF1-HBP的生长抑制作用比单独的BLF1-HBP至少高20倍。GALA3以pH依赖的方式有效地促进了BLF1-HBP的内体逃逸，并大大增强了BLF1-HBP的凋亡活性。综上所述，我们的数据表明，通过调节GALA的疏水性，我们获得了更有效的内体逃逸肽。因此，GALA3融合可以提高治疗性蛋白药物的效率。在不同肿瘤细胞系中，GALA3-BLF1-HBP的生长抑制作用比单独的BLF1-HBP至少高20倍。GALA3以pH依赖的方式有效地促进了BLF1-HBP的内体逃逸，并大大增强了BLF1-HBP的凋亡活性。综上所述，我们的数据表明，通过调节GALA的疏水性，我们获得了更有效的内体逃逸肽。因此，GALA3融合可以提高治疗性蛋白药物的效率。在不同肿瘤细胞系中，GALA3-BLF1-HBP的生长抑制作用比单独的BLF1-HBP至少高20倍。GALA3以pH依赖的方式有效地促进了BLF1-HBP的内体逃逸，并大大增强了BLF1-HBP的凋亡活性。综上所述，我们的数据表明，通过调节GALA的疏水性，我们获得了更有效的内体逃逸肽。因此，GALA3融合可以提高治疗性蛋白药物的效率。