RNA依赖性RNA聚合酶作为抗戊型肝炎病毒药物作用靶点的研究进展

Research Progress on RdRp as an Action Target for Anti-Hepatitis E Virus Drug

戊型肝炎病毒(Hepatitis E virus,HEV)是造成急性肝炎最常见的原因之一。HEV基因组由5′非编码区、3个开放阅读框(ORF1、ORF2、ORF3)和3′非编码区组成,仅在HEV-1中发现了ORF4,并与ORF1重叠。各种编码蛋白在HEV的复制和感染中发挥着不同的作用,而HEV的复制是由ORF1编码的RNA依赖性RNA聚合酶(RNA-dependent RNA polymerase,RdRp)所介导的。HEV RdRp是由多个蛋白亚基组成的复合酶,具有7个保守基序,这些保守基序在RNA合成过程中发挥核苷酸识别、合成、延伸、修饰和稳定等作用,保证了RdRp的功能,在HEV的复制和转录中起到关键作用。因此,以RdRp作为抗HEV药物作用靶点的治疗方案具有很好的应用前景,是目前药物开发的一种主流思路。目前,已发现利巴韦林、索非布韦、2′-C-甲基胞苷(2CMC)等核苷类RdRp抑制剂和锌、GPC-N114等非核苷类RdRp抑制剂对HEV有较强的抑制作用,可作为潜在的抗HEV药物进行深入研究。笔者对HEV编码蛋白和HEV RdRp的结构与功能进行阐述,总结目前发现的对HEV有抑制作用的RdRp抑制剂,以期为HEV的药物开发提供一种新的思路。

Hepatitis E virus(HEV)is one of the most common causes of acute hepatitis.The HEV genome consists of a 5′non-coding region,three open reading frames(ORF1,ORF2 and ORF3),and a 3′non-coding region,with ORF4 found only in HEV-1 and overlapping with ORF1.Various coding proteins play different roles in HEV replication and infection,and HEV replication is mediated by RNA-dependent RNA polymerase(RdRp)encoded by ORF1.HEV RdRp is a complex enzyme composed of multiple protein subunits,with 7 conserved motifs.These conserved motifs play roles in nucleotide recognition,addition,extension,modification,and stabilization during RNA synthesis,ensuring the functionality of RdRp,which plays a crucial role in HEV replication and transcription.Therefore,RdRp as the action target of anti-HEV drug has a good application prospect and is a mainstream idea in drug development.Currently,nucleoside RdRp inhibitors like ribavirin,sofosbuvir and 2CMC,and non-nucleoside RdRp inhibitors like zinc salts,GPC-N114 have shown strong inhibitory effects on HEV and can be potential anti-HEV drugs for further research.The author elaborates on the structure and function of HEV encoding protein and HEV RdRp,and a summary of the RdRp inhibitors that have been discovered to inhibit HEV is provided in order to offer new insights for the development of HEV drugs.