Sorrell Thomas, Liu Yujun, Liu Fenyong
School of Public Health, University of California, Berkeley, CA 94720, USA.
Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA.
Molecules. 2025 Sep 12;30(18):3725. doi: 10.3390/molecules30183725.
Nucleic acid-based gene-interfering molecules, such as antisense oligonucleotides, ribozymes, and small interfering RNA (siRNA), represent exciting gene-targeting agents for therapeutic applications. RNase P ribozymes derived from M1 RNA, the catalytic RNA subunit of RNase P in , have shown great promise as a novel nucleic acid-based gene interference approach to modulate gene expression. When M1 RNA is covalently linked to a guide sequence (GS), it can be engineered into a sequence-specific endonuclease M1GS ribozyme, which can hydrolyze any mRNA that base-pairs with the guide sequence. M1GS activity enhancement has been achieved through an in vitro selection process that introduced mutations into M1 RNA. This selection process generated ribozyme variants with improved cleavage efficiency and substrate affinity. Hepatitis B virus (HBV) chronically infects more than 250 million people worldwide and is the leading cause of cirrhosis and liver cancer globally. Current FDA-approved drugs cannot completely eliminate HBV chronic infections. RNase P ribozymes have recently been demonstrated to effectively inhibit HBV gene expression and replication in human cells. This review summarizes the recent progress in using RNase P ribozymes to inhibit HBV infection and discusses prospects for developing engineered RNase P ribozymes for therapeutic applications against HBV infection and associated diseases.
基于核酸的基因干扰分子，如反义寡核苷酸、核酶和小干扰RNA（siRNA），是用于治疗应用的令人兴奋的基因靶向剂。源自M1 RNA（大肠杆菌中RNase P的催化RNA亚基）的RNase P核酶，作为一种新型的基于核酸的基因干扰方法来调节基因表达，已显示出巨大的前景。当M1 RNA与引导序列（GS）共价连接时，它可以被设计成序列特异性内切核酸酶M1GS核酶，该酶可以水解任何与引导序列碱基配对的mRNA。通过将突变引入M1 RNA的体外筛选过程实现了M1GS活性的增强。这个筛选过程产生了具有更高切割效率和底物亲和力的核酶变体。乙型肝炎病毒（HBV）在全球范围内慢性感染超过2.5亿人，是全球肝硬化和肝癌的主要原因。目前美国食品药品监督管理局（FDA）批准的药物不能完全消除HBV慢性感染。最近已证明RNase P核酶能有效抑制人细胞中HBV的基因表达和复制。这篇综述总结了使用RNase P核酶抑制HBV感染的最新进展，并讨论了开发工程化RNase P核酶用于治疗HBV感染及相关疾病的前景。
