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

doi:10.16431/j.cnki.1671-7236.2024.10.037

Abstract

Abstract: 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.

Key words: Hepatitis E virus (HEV); RNA-dependent RNA polymerase (RdRp); drug development

CLC Number:

S852.65
R373

HE Zhenwen, LIU Dingyu, LIU Baoling, ZHANG Pian, WANG Xiaohu, WANG Gang, HUANG Yuan, CHEN Jing, LIU Wenjun, CAI Rujian. Research Progress on RdRp as an Action Target for Anti-Hepatitis E Virus Drug[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(10): 4568-4577.

References

[1] GENG Y,SHI T,WANG Y.Epidemiology of hepatitis E[J].Advances in Experimental Medicine and Biology,2023,1417:33-48.
[2] WANG Y,ZHAO C,QI Y,et al.Hepatitis E virus[J].Advances in Experimental Medicine and Biology,2016:948:1-16.
[3] 卓娜,朱忠武,李静,等.猪源戊型肝炎病毒ORF2蛋白生物信息学分析及真核表达研究[J].中国畜牧兽医,2023,50(5):1959-1970.ZHOU N,ZHU Z W,LI J,et al.Bioinformatics analysis and eukaryotic expression of ORF2 protein of swine Hepatitis E virus[J].China Animal Husbandry & Veterinary Medicine,2023,50(5):1959-1970.(in Chinese)
[4] 焦寒伟,周志雄,李梦娟,等.猪戊型肝炎病毒ORF3蛋白影响HepG2细胞核黄素代谢的lncRNA-mRNA调控网络的鉴定[J].中国畜牧兽医,2021,48(12):4618-4627.JIAO H W,ZHOU Z X,LI M J,et al.Identification of lncRNA-mRNA regulatory network of riboflavin metabolism in hepG2 cell affected by swine Hepatitis E virus ORF3 protein[J].China Animal Husbandry & Veterinary Medicine,2021,48(12):4618-4627.(in Chinese)
[5] YADAV K K,BOLEY P A,FRITTS Z,et al.Ectopic expression of genotype 1 Hepatitis E virus ORF4 increases genotype 3 HEV viral replication in cell culture[J]. Viruses,2021,13(1):75.
[6] TE VELTHUIS A J.Common and unique features of viral RNA-dependent polymerases[J].Cellular and Molecular Life Sciences,2014,71(22):4403-4420.
[7] DALTON H R,KAMAR N.Treatment of Hepatitis E virus[J].Current Opinion in Infectious Diseases,2016,29(6):639-644.
[8] DAO THI V L,DEBING Y,WU X,et al.Sofosbuvir inhibits Hepatitis E virus replication in vitro and results in an additive effect when combined with ribavirin[J].Gastroenterology,2016,150(1):82-85.
[9] GORIS N,DE PALMA A,TOUSSAINT J F,et al.2'-C-methylcytidine as a potent and selective inhibitor of the replication of Foot-and-mouth disease virus[J].Antiviral Research,2007,73(3):161-168.
[10] PURDY M A,DREXLER J F,MENG X J,et al.ICTV virus taxonomy profile:Hepeviridae 2022[J].Journal of General Virology,2022,103(9):10.
[11] RAJI Y E,TOUNG O P,TAIB N M,et al.Hepatitis E virus:An emerging enigmatic and underestimated pathogen[J].Saudi Journal of Biological Sciences,2022,29(1):499-512.
[12] SRIDHAR S,TENG J L L,CHIU T H,et al.Hepatitis E virus genotypes and evolution:Emergence of camel hepatitis E variants[J].International Journal of Molecular Sciences,2017,18(4):869.
[13] AGGARWAL R.Hepatitis E:Historical,contemporary and future perspectives[J].Journal of Gastroenterology and Hepatology,2011,26(Suppl 1):72-82.
[14] EMERSON S U,NGUYEN H T,TORIAN U,et al.An essential RNA element resides in a central region of Hepatitis E virus ORF2[J].The Journal of General Virology,2013,94(Pt 7):1468-1476.
[15] KANNAN H,FAN S,PATEL D,et al.The Hepatitis E virus open reading frame 3 product interacts with microtubules and interferes with their dynamics[J].Journal of Virology,2009,83(13):6375-6382.
[16] NAGASHIMA S,TAKAHASHI M,JIRINTAI,et al.A PSAP motif in the ORF3 protein of Hepatitis E virus is necessary for virion release from infected cells[J].The Journal of General Virology,2011,92(2):269-278.
[17] KAR-ROY A,KORKAVA H,OBEROI R,et al.The hepatitis E virus open reading frame 3 protein activates ERK through binding and inhibition of the MAPK phosphatase[J].The Journal of Biological Chemistry,2004,279(27):28345-28357.
[18] MOIN S M,PANTEVA M,JAMEEL S.The Hepatitis E virus Orf3 protein protects cells from mitochondrial depolarization and death[J].The Journal of Biological Chemistry,2007,282(29):21124-21133.
[19] ROPP S L,TAM A W,BEAMES B,et al.Expression of the Hepatitis E virus ORF1[J].Archives of Virology,2000,145(7):1321-1337.
[20] PARVEZ M K.The Hepatitis E virus ORF1'X-domain’residues form a putative macrodomain protein/Appr-1"-pase catalytic-site,critical for viral RNA replication[J].Gene,2015,566(1):47-53.
[21] OJHA N K,LOLE K S.Hepatitis E virus ORF1 encoded nonstructural protein-host protein interaction network[J]. Virus Research,2016,213:195-204.
[22] KARPE Y A,LOLE K S.NTPase and 5' to 3' RNA duplex-unwinding activities of the Hepatitis E virus helicase domain[J].Journal of Virology,2010,84(7):3595-3602.
[23] AGRAWAL S,GUPTA D,PANDA S K.The 3' end of Hepatitis E virus (HEV) genome binds specifically to the viral RNA-dependent RNA polymerase (RdRp)[J].Virology,2001,282(1):87-101.
[24] KOONIN E V.The phylogeny of RNA-dependent RNA polymerases of positive-strand RNA viruses[J].The Journal of General Virology,1991,72(9):2197-2206.
[25] MAHILKAR S,PAINGANKAR M S,LOLE K S.Hepatitis E virus RNA-dependent RNA polymerase:RNA template specificities,recruitment and synthesis[J].The Journal of General Virology,2016,97(9):2231-2242.
[26] NG K K,ARNOLD J J,CAMERON C E.Structure-function relationships among RNA-dependent RNA polymerases[J].Current Topics in Microbiology and Immunology,2008,320:137-156.
[27] AHLQUIST P.RNA-dependent RNA polymerases,viruses,and RNA silencing[J].Science,2002,296(5571):1270-1273.
[28] AČG ERN AY＇G J, AČG ERNÁ BOLFÍKOVÁ B,VALDÉS J J,et al.Evolution of tertiary structure of viral RNA dependent polymerases[J]. Public Library of Science One,2014，9(5):e96070.
[29] LANG D M,ZEMLA A T,ZHOU C L.Highly similar structural frames link the template tunnel and NTP entry tunnel to the exterior surface in RNA-dependent RNA polymerases[J].Nucleic Acids Research,2013,41(3):1464-1482.
[30] WANG M,LI R,SHU B,et al.Stringent control of the RNA-dependent RNA polymerase translocation revealed by multiple intermediate structures[J].Nature Communications,2020,11(1):2605.
[31] ARRIGA D,FERRER-ORTA C,QUEROL-AUDÍ J,et al.Role of motif B loop in allosteric regulation of RNA-dependent RNA polymerization activity[J].Journal of Molecular Biology,2013,425(13):2279-2287.
[32] WANG Y,XIAO M,CHEN J,et al.Mutational analysis of the GDD sequence motif of Classical swine fever virus RNA-dependent RNA polymerases[J].Virus Genes,2007,34(1):63-65.
[33] FERRERO D S,FALQUI M,VERDAGUER N.Snapshots of a non-canonical RdRP in action[J].Viruses,2021,13(7):1260.
[34] KIDMOSE R T,VASILIEV N N,CHETVERIN A B,et al.Structure of the Qbeta replicase,an RNA-dependent RNA polymerase consisting of viral and host proteins[J].Proceedings of the National Academy of Sciences of the United States of America,2010,107(24):10884-10889.
[35] JÁCOME R,BECERRA A,PONCE DE LEÓN S,et al.Structural analysis of monomeric RNA-dependent polymerases:Evolutionary and therapeutic implications[J].Public Library of Science One,2015，10(9):e0139001.
[36] CHU C,FAN S,LI C,et al.Functional analysis of conserved motifs in Influenza virus PB1 protein[J].Public Library of Science One,2012,7(5):e36113.
[37] GARRIGA D,NAVARRO A,QUEROL-AUDÍ J,et al.Activation mechanism of a noncanonical RNA-dependent RNA polymerase[J].Proceedings of the National Academy of Sciences of the United States of America,2007，104(51):20540-20545.
[38] JIA H,GONG P.A structure-function diversity survey of the RNA-dependent RNA polymerases from the positive-strand RNA viruses[J].Frontiers in Microbiology,2019,10:1945.
[39] KUMAR R,MISHRA S,SHREYA,et al.Recent advances in the discovery of potent RNA-dependent RNA-polymerase (RdRp) inhibitors targeting viruses[J].Royal Society of Chemistry,2020,12(3):306-320.
[40] PICARAZZI F,VICENTI I,SALADINI F,et al.Targeting the RdRp of emerging RNA viruses:The structure-based drug design challenge[J].Molecules,2020,25(23):5695.
[41] 王超,吴润,刘光清.正链RNA病毒复制酶结构与功能研究进展[J].中国动物传染病学报,2011,19(5):76-82.WANG C,WU R,LIU G Q.Structure and functions of RNA-dependent RNA polymerase of positive-strand RNA viruses[J].Chinese Journal of Veterinary Parasitology, 2011,19(5):76-82.(in Chinese)
[42] LEITE D R B,MANTOVANI K M,CORDEIRO S P,et al.RNA-dependent RNA polymerase (RdRp) natural antiviral inhibitors:A review[J].Medicinal Chemistry Research,2022,31(12):2089-2102.
[43] HURWITZ S J,SCHINAZI R F.Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors[J].Current Opinion in HIV and AIDS,2013,8(6):556-564.
[44] NYANGUILE O,DEVOGELAERE B,VIJGEN L,et al.1a/1b subtype profiling of nonnucleoside polymerase inhibitors of Hepatitis C virus[J].Journal of Virology,2010,84(6):2923-2934.
[45] TAM R C,RAMASAMY K,BARD J,et al.The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviral effects with retention of both immunomodulatory activity and reduction of hepatitis-induced serum alanine aminotransferase levels[J].Antimicrobial Agents and Chemotherapy, 2000,44(5):1276-1283.
[46] VIGNUZZI M,STONE J K,ANDINO R.Ribavirin and lethal mutagenesis of Poliovirus:Molecular mechanisms,resistance and biological implications[J].Virus Research,2005,107(2):173-181.
[47] CROTTY S,CAMERON C E,ANDINO R.RNA virus error catastrophe:Direct molecular test by using ribavirin[J].Proceedings of the National Academy of Sciences of the United States of America,2001,98(12):6895-6900.
[48] LOUSTAUD-RATTI V,DEBETTE-GRATIEN M,JACQUES J,et al.Ribavirin:Past,present and future[J].World Journal of Hepatology,2016,8(2):123-130.
[49] WAHID B.Successful treatment of HBV,HCV,& HEV,with 12-week long use of tenofovir,sofosbuvir,daclatasvir,and ribavirin:A case report[J].Journal of Infection and Public Health,2020,13(1):149-150.
[50] KAMAR N,IZOPET J,TRIPON S,et al.Ribavirin for chronic Hepatitis E virus infection in transplant recipients[J].The New England Journal of Medicine,2014,370(12):1111-1120.
[51] BALATOW P,SANDLIN A,CORY T J.An evaluation of ledipasvir + sofosbuvir for the treatment of chronic hepatitis C infection[J].Expert Opinion on Pharmacotherapy,2021,22(14):1839-1846.
[52] FELD J J.Interferon-free strategies with a nucleoside/nucleotide analogue[J].Seminars in Liver Disease,2014,34(1):37-46.
[53] VAN DER VALK M,ZAAIJER H L,KATER A P,et al.Sofosbuvir shows antiviral activity in a patient with chronic Hepatitis E virus infection[J].Journal of Hepatology,2017,66(1):242-243.
[54] BILIOTTI E,FRANCHI C,SPAZIANTE M,et al.Autochthonous acute hepatitis E:Treatment with sofosbuvir and ribavirin[J].Infection,2018,46(5):725-727.
[55] GARDELLI C,ATTENNI B,DONGHI M,et al.Phosphoramidate prodrugs of 2'-C-methylcytidine for therapy of Hepatitis C virus infection[J].Journal of Medicinal Chemistry,2009,52(17):5394-5407.
[56] LEE J C,TSENG C K,WU Y H,et al.Characterization of the activity of 2'-C-methylcytidine against Dengue virus replication[J].Antiviral Research,2015,116:1-9.
[57] ROCHA-PEREIRA J,JOCHMANS D,DALLMEIER K,et al.Inhibition of Norovirus replication by the nucleoside analogue 2'-C-methylcytidine[J].Biochemical and Biophysical Research Communications,2012,427:796-800.
[58] QU C,XU L,YIN Y,et al.Nucleoside analogue 2'-C-methylcytidine inhibits Hepatitis E virus replication but antagonizes ribavirin[J].Archives of Virology,2017,162(10):2989-2996.
[59] FENG J Y,XU Y,BARAUSKAS O,et al.Role of mitochondrial RNA polymerase in the toxicity of nucleotide inhibitors of Hepatitis C virus[J].Antimicrobial Agents and Chemotherapy,2015,60(2):806-817.
[60] READ S A,OBEID S,AHLENSTIEL C,et al.The role of zinc in antiviral immunity[J]. Advances in Nutrition,2019,10(4):696-710.
[61] SUARA R O,CROWE J E JR.Effect of zinc salts on Respiratory syncytial virus replication[J].Antimicrob Agents Chemother,2004,48(3):783-790.
[62] TALLEY D C,DELANG L,NEYTS J,et al.Exploring the importance of zinc binding and steric/hydrophobic factors in novel HCV replication inhibitors[J].Bioorganic and Medicinal Chemistry Letters,2016,26(4):1196-1199.
[63] KAUSHIK N,SUBRAMANI C,ANANG S,et al.Zinc salts block Hepatitis E virus replication by inhibiting the activity of viral RNA-dependent RNA polymerase[J].Journal of Virology,2017,91(21):e00754-17.
[64] KAUSHIK N,ANANG S,GANTI K P,et al.Zinc:A potential antiviral against Hepatitis E virus infection?[J].DNA and Cell Biology,2018,37(7):593-599.
[65] HAASE H,RINK L.Zinc signals and immune function[J].International Union of Biochemistry,2014,40(1):27-40.
[66] VAN DER LINDEN L,VIVES-ADRIÁN L,SELISKO B,et al.The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family[J]. PLoS Pathogens,2015，11(3):e1004733.
[67] NETZLER N E,ENOSI TUIPULOTU D,VAASUDEVAN S G,et al.Antiviral candidates for treating Hepatitis E virus infection[J].Antimicrobial Agents and Chemotherapy,2019,63(6):e00003-19.
[68] 刘丁语,何振文,刘宝玲,等.戊型肝炎病毒研究进展[J].中国畜牧兽医,2024,51(2):736-747.LIU D Y,HE Z W,LIU B L,et al.Advances in research on Hepatitis E virus[J].China Animal Husbandry & Veterinary Medicine,2024,51(2):736-747.(in chinese)
[69] HUI W,WEI L.Treatment of hepatitis E[J].Advances in Experimental Medicine and Biology,2023,1417:215-226.

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

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 3

Recommended Articles

Metrics

Comments

[1]	HE Zhenwen, LIU Dingyu, LIU Baoling, ZHANG Pian, WANG Xiaohu, WANG Gang, HUANG Yuan, CHEN Jing, DU Zongliang, CAI Rujian. Research Progress on Cross-species Transmission and Prevention and Control Techniques of Hepatitis E Virus [J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(6): 2605-2620.
[2]	LIU Dingyu, HE Zhenwen, LIU Baoling, WANG Gang, WANG Xiaohu, TAN Chen, CAI Rujian. Advances in Research on Hepatitis E Virus [J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(2): 736-747.
[3]	JIAO Hanwei, ZHOU Zhixiong, LI Mengjuan, XIAO Yu, LI Bowen, GUO Xiaoyi, ZENG Hui, GU Guojing, SHUAI Xuehong. Identification of lncRNA-mRNA Regulatory Network of Riboflavin Metabolism in HepG2 Cells Affected by Swine Hepatitis E Virus ORF3 Protein [J]. China Animal Husbandry and Veterinary Medicine, 2021, 48(12): 4618-4627.