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基因编码的LYTACs的定向进化用于细胞介导的传递

Jonathan Lee Yang^1,2, Sean A Yamada-Hunter³, Louai Labanieh^3,4,5

¹Department of Chemistry, Stanford University, Stanford, CA 94305.

Proceedings of the National Academy of Sciences of the United States of America

|March 21, 2024

概括

我们通过用IGF2.2替代合成来开发一种可遗传编码的化体向化体 (GELYTAC). 这一创新使治疗细胞能够在疾病部位提供GELYTAC用于向蛋白质降解.

科学领域:

生物技术是生物技术.
分子生物学分子生物学
治疗药物开发治疗药物开发

背景情况:

lysosome-targeting chimeras (LYTACs) 为细胞外蛋白质降解提供了一个新的治疗策略.
现有的LYTACs利用合成糖,限制它们的遗传编码和细胞集成.

研究的目的:

设计和开发一个完全可遗传编码的LYTAC (GELYTAC).
为了使LYTAC技术能够集成到治疗细胞中,以实现有针对性的输送和蛋白质降解.
为了增强GELYTAC的功效和细胞中的分泌.

主要方法:

用胰岛素样生长因子2 (IGF2) 取代LYTACs的糖成分.
采用定向进化来提高GELYTAC的疗效和功效.
在HEK293T细胞和人类T细胞中验证了GELYTAC的分泌和功能.

主要成果:

通过使用IGF2.2成功设计了一种可转基因编码的LYTAC (GELYTAC).
通过定向进化证明了GELYTAC功效的增强.
从细胞系和初级T细胞中确认了功能GELYTAC的分泌,促进了蛋白的吸收和降解.

结论:

凝代表了针对性蛋白质降解技术的重大进步.
基因编码的LYTAC可以集成到免疫细胞中,用于局部治疗.
编造的分泌GELYTAC的免疫细胞对空间选择性蛋白质降解疗法充满希望.

关键词:

细胞治疗疗法细胞治疗疗法蛋白质工程工程蛋白质工程有针对性的蛋白质降解降解.

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