工程化胺丰富增强内体逃生,用于针对抗体的功能性蛋白质的细胞内传递

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Yan Zhao^1,2, Haolin Jiang^1,3, Jiazhen Yu¹

¹School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, China.

Angewandte Chemie (International ed. in English)

|June 7, 2023

概括

研究人员开发了pH敏感,将治疗性蛋白质输送到细胞中,克服了内分体捕获. 这一策略使得针对癌症治疗和基因编辑应用的细胞内输送成为可能.

科学领域:

生物化学生物化学
分子生物学分子生物学
药物运输药物运输药物运输

背景情况:

蛋白质/治疗药物的临床应用仅限于细胞外点,这是由于内体陷.
治疗性蛋白质的细胞内输送仍然是医学上的重大挑战.

研究的目的:

设计,使蛋白质治疗药物的内分体到细胞质的传递成为可能.
设计模块化融合蛋白质,用于针对性地在细胞内输送治疗载荷.

主要方法:

通过用histidine替换Arg/Lys残留物来创建pH依赖的修改的阴离子细胞透 (CPPs).
工程模块化融合蛋白质结合胺丰富 (hsLMWP) 进行抗体向的输送.
在试验室中测试了像BID和Cre这样的货物的运输,将其重新组合成癌细胞.
在异种移植小鼠中评估了trastuzumab-hsLMWP-BID融合的体内抗瘤疗效.

主要成果:

开发出具有高内分体逃逸能力的富含胺 (hsLMWP).
实现了针对抗体的多种蛋白质载荷 (例如,BID,Cre重组酶) 的细胞交付到多种癌细胞类型中.
在体内经过trastuzumab-hsLMWP-BID融合的显著抗瘤疗效,没有明显的副作用.

结论:

富含希斯蒂丁的类策略有效地克服了细胞内蛋白质输送的内体捕获.
模块化融合蛋白为各种应用提供了一个多功能平台,用于针对性地提供治疗蛋白质.
这种方法有望促进癌症治疗,基因编辑和免疫治疗的发展.

关键词:

用抗体向的输送细胞质输送细胞质输送药物运输药物运输药物运输细胞内体逃生细胞内体逃生酸是一种酸.

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