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一个高通量平台来识别CRISPR-Cas9的小分子抑制剂

Basudeb Maji¹, Soumyashree A Gangopadhyay¹, Miseon Lee²

¹Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Divisions of Renal Medicine and Engineering, Brigham and Women's Hospital, Boston, MA 02115, USA.

|May 4, 2019

概括

科学家开发了第一种合成的小分子来控制CRISPR-Cas9基因编辑. 这些细胞透性抑制剂提供了对基因组工程技术的精确,可逆控制.

科学领域:

分子生物学
生物化学
化学生物学

背景情况:

精确控制CRISPR-Cas9对于基因组工程的进步至关重要.
现有的控制CRISPR-Cas9活动的方法存在局限性.
开发小分子抑制剂为调节CRISPR-Cas9提供了一种新方法.

研究的目的:

开发一个可通用的平台来识别Streptococcus pyogenes Cas9 (SpCas9) 的合成小分子抑制剂.
为精确控制 SpCas9 活性,制造细胞通透,可逆和稳定的抑制剂.
建立一种快速识别SpCas9和相关核酶的抑制剂的方法.

主要方法:

开发了SpCas9功能的高通量测定,包括原空间器相邻动机结合.
选了一系列与天然产品类似的小分子.
使用结构-活性关系来确定SpCas9抑制的药.

主要成果:

确定了第一个具有细胞通透性,可逆性和稳定的SpCas9合成小分子抑制剂 (<500Da).
已经证明了SpCas9的剂量和时间控制以及包括转录激活在内的催化受损的SpCas9技术.
确立了SpCas9抑制的药.

结论:

已经建立了一个可通用的平台来发现合成,微型,细胞透和可逆的SpCas9抑制剂.
这些小分子提供了对CRISPR- Cas9活性的精确时间和剂量依赖的控制.
该平台可以扩展到识别下一代CRISPR相关核酶的抑制剂.

关键词:

在CRISPR-Cas9中其他类型基础编辑 dCas9 在基因组编辑高通量选小分子抑制剂合成抗CRISPR药物转录激活

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