Chen Siwei, Chen Deng, Liu Bin, Haisma Hidde J
Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen 9713 AV, the Netherlands.
Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen 9713 AV, the Netherlands; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA(1).
Drug Discov Today. 2022 Apr;27(4):951-966. doi: 10.1016/j.drudis.2021.11.018. Epub 2021 Nov 22.
Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genome engineering has become a standard procedure for creating genetic and epigenetic changes of DNA molecules in basic biology, biotechnology, and medicine. However, its versatile applications have been hampered by its overall low precise gene modification efficiency and uncontrollable prolonged Cas9 activity. Therefore, overcoming these problems could broaden the therapeutic use of CRISPR/Cas9-based technologies. Here, we review small molecules with the clinical potential to precisely modulate CRISPR/Cas9-mediated genome-editing activity and discuss their mechanisms of action. Based on these data, we suggest that direct-acting small molecules for Cas9 are more suitable for precisely regulating Cas9 activity. These findings provide useful information for the identification of novel small-molecule enhancers and inhibitors of Cas9 and Cas9-associated endonucleases.
成簇规律间隔短回文重复序列/CRISPR相关蛋白9（CRISPR/Cas9）介导的基因组工程已成为在基础生物学、生物技术和医学中对DNA分子进行遗传和表观遗传改变的标准程序。然而，其广泛应用受到整体低精确基因编辑效率和不可控的Cas9活性延长的阻碍。因此，克服这些问题可以拓宽基于CRISPR/Cas9技术的治疗用途。在这里，我们综述了具有精确调节CRISPR/Cas9介导的基因组编辑活性临床潜力的小分子，并讨论了它们的作用机制。基于这些数据，我们认为针对Cas9的直接作用小分子更适合精确调节Cas9活性。这些发现为鉴定新型Cas9和Cas9相关核酸内切酶的小分子增强剂和抑制剂提供了有用信息。
