{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T21:42:20Z","timestamp":1793137340604,"version":"4.5.0"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Gastroenterol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>NS5A and NS5B proteins of hepatitis C virus (HCV) are the main targets of compounds that directly inhibit HCV infections. However, the emergence of resistance-associated substitutions (RASs) may cause substantial reductions in susceptibility to inhibitors.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Viral load and genotyping were determined in eighty-seven na\u00efve HCV-infected patients, and the amplified NS5A and NS5B regions were sequenced by Sanger sequencing. In addition, physicochemical properties, structural features, immune epitopes, and inhibitors-protein interactions of sequences were analyzed using several bioinformatics tools.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Several amino acid residue changes were found in NS5A and NS5B proteins; however, we did not find any mutations related to resistance to the treatment in NS5B. Different phosphorylation and few glycosylation sites were assessed. Disulfide bonds were identified in both proteins that had a significant effect on the function and structure of HCV proteins. Applying reliable software to predict B-cell epitopes, 3 and 5 regions were found for NS5A and NS5B, respectively, representing a considerable potential to induce the humoral immune system. Docking analysis determined amino acids involved in the interaction of inhibitors and mentioned proteins may not decrease the drug efficiency.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Strong interactions between inhibitors, NS5A and NS5B proteins and the lack of efficient drug resistance mutations in the analyzed sequences may confirm the remarkable ability of NS5A and NS5B inhibitors to control HCV infection amongst Iranian patients. The results of bioinformatics analysis could unveil all features of both proteins, which can be beneficial for further investigations on HCV drug resistance and designing novel vaccines.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12876-021-01988-y","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T18:02:28Z","timestamp":1637776948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["First report on molecular docking analysis and drug resistance substitutions to approved HCV NS5A and NS5B inhibitors amongst Iranian patients"],"prefix":"10.1186","volume":"21","author":[{"given":"Zahra","family":"Hasanshahi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ava","family":"Hashempour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzane","family":"Ghasabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javad","family":"Moayedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra","family":"Musavi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Behzad","family":"Dehghani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidar","family":"Sharafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Joulaei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"issue":"5","key":"1988_CR1","first-page":"214","volume":"58","author":"J Moayedi","year":"2020","unstructured":"Moayedi J, Hashempour T, Musavi Z, Dehghani B, Hasanshahi Z, Merat S. The predictive factors for favorable outcomes of peginterferon and ribavirin combination therapy in HCV-infected patients. Acta Med Iran. 2020;58(5):214\u201320.","journal-title":"Acta Med Iran"},{"issue":"11","key":"1988_CR2","doi-asserted-by":"publisher","first-page":"2902","DOI":"10.3748\/wjg.v20.i11.2902","volume":"20","author":"S Nakamoto","year":"2014","unstructured":"Nakamoto S, Kanda T, Wu S, Shirasawa H, Yokosuka O. Hepatitis C virus NS5A inhibitors and drug resistance mutations. World J Gastroenterol. 2014;20(11):2902\u201312.","journal-title":"World J Gastroenterol"},{"issue":"47","key":"1988_CR3","doi-asserted-by":"publisher","first-page":"48576","DOI":"10.1074\/jbc.M407787200","volume":"279","author":"TL Tellinghuisen","year":"2004","unstructured":"Tellinghuisen TL, Marcotrigiano J, Gorbalenya AE, Rice CM. The NS5A protein of hepatitis C virus is a zinc metalloprotein. J Biol Chem. 2004;279(47):48576\u201387.","journal-title":"J Biol Chem"},{"issue":"4","key":"1988_CR4","doi-asserted-by":"publisher","first-page":"2320","DOI":"10.1128\/JVI.02861-12","volume":"87","author":"RA Fridell","year":"2013","unstructured":"Fridell RA, Valera L, Qiu D, Kirk MJ, Wang C, Gao M. Intragenic complementation of hepatitis C virus NS5A RNA replication-defective alleles. J Virol. 2013;87(4):2320\u20139.","journal-title":"J Virol"},{"issue":"3","key":"1988_CR5","first-page":"173","volume":"33","author":"AM Alborzi","year":"2015","unstructured":"Alborzi AM, Bamdad T, Davoodian P, Hashempoor T, Nejatizadeh AA, Moayedi J. Insights into the role of HCV plus-\/minus strand RNA, IFN-\u03b3 and IL-29 in relapse outcome in patients infected with HCV. Asian Pac J Allergy Immunol. 2015;33(3):173\u201381.","journal-title":"Asian Pac J Allergy Immunol"},{"issue":"2","key":"1988_CR6","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/s00430-017-0497-y","volume":"206","author":"A Alborzi","year":"2017","unstructured":"Alborzi A, Hashempour T, Moayedi J, Musavi Z, Pouladfar G, Merat S. Role of serum level and genetic variation of IL-28B in interferon responsiveness and advanced liver disease in chronic hepatitis C patients. Med Microbiol Immunol. 2017;206(2):165\u201374.","journal-title":"Med Microbiol Immunol"},{"issue":"9","key":"1988_CR7","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1136\/gut.2005.076646","volume":"55","author":"M Manns","year":"2006","unstructured":"Manns M, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut. 2006;55(9):1350\u20139.","journal-title":"Gut"},{"issue":"34652","key":"1988_CR8","first-page":"1","volume":"6","author":"S Nitta","year":"2016","unstructured":"Nitta S, Asahina Y, Matsuda M, Yamada N, Sugiyama R, Masaki T, et al. Effects of resistance-associated NS5A mutations in hepatitis C virus on viral production and susceptibility to antiviral reagents. Sci Rep. 2016;6(34652):1\u20139.","journal-title":"Sci Rep"},{"issue":"1","key":"1988_CR9","first-page":"55","volume":"28","author":"A Alexopoulou","year":"2015","unstructured":"Alexopoulou A, Karayiannis P. Interferon-based combination treatment for chronic hepatitis C in the era of direct acting antivirals. Ann Gastroenterol. 2015;28(1):55\u201365.","journal-title":"Ann Gastroenterol"},{"issue":"9","key":"1988_CR10","doi-asserted-by":"publisher","first-page":"543","DOI":"10.4254\/wjh.v10.i9.543","volume":"10","author":"H Sharafi","year":"2018","unstructured":"Sharafi H, Alavian SM. Hepatitis C resistance to NS5A inhibitors: Is it going to be a problem? World J Hepatol. 2018;10(9):543\u20138.","journal-title":"World J Hepatol"},{"issue":"6","key":"1988_CR11","doi-asserted-by":"publisher","first-page":"e14248","DOI":"10.5812\/hepatmon.14248","volume":"17","author":"M Petronella Gededzha","year":"2017","unstructured":"Petronella Gededzha M, Mphahlele MJ, Blackard JT, Gloria SS. Prevalence of NS5B resistance mutations in hepatitis C virus (HCV) treatment naive South Africans. Hepat Mon. 2017;17(6):e14248.","journal-title":"Hepat Mon"},{"issue":"13","key":"1988_CR12","doi-asserted-by":"publisher","first-page":"3524","DOI":"10.1080\/07391102.2018.1519460","volume":"37","author":"H Dorosti","year":"2019","unstructured":"Dorosti H, Eslami M, Negahdaripour M, Ghoshoon MB, Gholami A, Heidari R, et al. Vaccinomics approach for developing multi-epitope peptide pneumococcal vaccine. J Biomol Struct Dyn. 2019;37(13):3524\u201335.","journal-title":"J Biomol Struct Dyn"},{"issue":"10","key":"1988_CR13","doi-asserted-by":"publisher","first-page":"2546","DOI":"10.1080\/07391102.2018.1491890","volume":"37","author":"S Sabetian","year":"2019","unstructured":"Sabetian S, Nezafat N, Dorosti H, Zarei M, Ghasemi Y. Exploring dengue proteome to design an effective epitope-based vaccine against dengue virus. J Biomol Struct Dyn. 2019;37(10):2546\u201363.","journal-title":"J Biomol Struct Dyn"},{"key":"1988_CR14","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1385\/1-59259-890-0:571","volume-title":"Protein identification and analysis tools on the ExPASy server. The proteomics protocols handbook","author":"E Gasteiger","year":"2005","unstructured":"Gasteiger E, Hoogland C, Gattiker A, Wilkins MR, Appel RD, Bairoch A. Protein identification and analysis tools on the ExPASy server. The proteomics protocols handbook. Springer; 2005. p. 571\u2013607."},{"key":"1988_CR15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/157016461701190801112325","volume":"17","author":"H Tayebeh","year":"2020","unstructured":"Tayebeh H, Behzad D, Zahra M, Tahereh A, Zahra H, Javad M, et al. Association of mutations in the NS5A-PKRBD region and IFNL4 genotypes with hepatitis C interferon responsiveness and its functional and structural analysis. Curr Proteom. 2020;17:1\u201312.","journal-title":"Curr Proteom"},{"issue":"3","key":"1988_CR16","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1093\/nar\/gkh253","volume":"32","author":"LM Iakoucheva","year":"2004","unstructured":"Iakoucheva LM, Radivojac P, Brown CJ, O\u2019Connor TR, Sikes JG, Obradovic Z, et al. The importance of intrinsic disorder for protein phosphorylation. Nucleic Acids Res. 2004;32(3):1037\u201349.","journal-title":"Nucleic Acids Res"},{"issue":"6","key":"1988_CR17","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1002\/pmic.200300771","volume":"4","author":"N Blom","year":"2004","unstructured":"Blom N, Sicheritz-Pont\u00e9n T, Gupta R, Gammeltoft S, Brunak S. Prediction of post-translational glycosylation and phosphorylation of proteins from the amino acid sequence. Proteomics. 2004;4(6):1633\u201349.","journal-title":"Proteomics"},{"issue":"6","key":"1988_CR18","doi-asserted-by":"publisher","first-page":"e67008","DOI":"10.1371\/journal.pone.0067008","volume":"8","author":"JS Chauhan","year":"2013","unstructured":"Chauhan JS, Rao A, Raghava GP. In silico platform for prediction of N-, O-and C-glycosites in eukaryotic protein sequences. PLoS ONE. 2013;8(6):e67008.","journal-title":"PLoS ONE"},{"key":"1988_CR19","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1093\/nar\/gkl189","volume":"34","author":"F Ferre","year":"2006","unstructured":"Ferre F, Clote P. DiANNA 1.1: an extension of the DiANNA web server for ternary cysteine classification. Nucleic Acids Res. 2006;34:182\u20135.","journal-title":"Nucleic Acids Res"},{"key":"1988_CR20","doi-asserted-by":"crossref","unstructured":"Saha S, Raghava GP. Prediction methods for B-cell epitopes. Immunoinformatics. 2007;387\u201394.","DOI":"10.1007\/978-1-60327-118-9_29"},{"key":"1988_CR21","doi-asserted-by":"crossref","unstructured":"Saha S, Raghava GPS, editors. BcePred: prediction of continuous B-cell epitopes in antigenic sequences using physico-chemical properties. In: International conference on artificial immune systems; 2004. Springer.","DOI":"10.1007\/978-3-540-30220-9_16"},{"issue":"6","key":"1988_CR22","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1093\/bioinformatics\/11.6.681","volume":"11","author":"C Geourjon","year":"1995","unstructured":"Geourjon C, Deleage G. SOPMA: significant improvements in protein secondary structure prediction by consensus prediction from multiple alignments. Bioinformatics. 1995;11(6):681\u20134.","journal-title":"Bioinformatics"},{"issue":"6","key":"1988_CR23","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nprot.2015.053","volume":"10","author":"LA Kelley","year":"2015","unstructured":"Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10(6):845\u201358.","journal-title":"Nat Protoc"},{"issue":"40","key":"1988_CR24","first-page":"1","volume":"9","author":"Y Zhang","year":"2008","unstructured":"Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinform. 2008;9(40):1\u20138.","journal-title":"BMC Bioinform"},{"issue":"26","key":"1988_CR25","doi-asserted-by":"publisher","first-page":"2057","DOI":"10.1007\/s10989-019-10002-9","volume":"2020","author":"B Dehghani","year":"2020","unstructured":"Dehghani B, Hasanshahi Z, Hashempour T. HIV capsid and protease, new targets of melittin. Int J Pept Res Ther. 2020;2020(26):2057\u201365.","journal-title":"Int J Pept Res Ther"},{"issue":"1","key":"1988_CR26","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1093\/nar\/gkt458","volume":"41","author":"L Heo","year":"2013","unstructured":"Heo L, Park H, Seok C. GalaxyRefine: protein structure refinement driven by side-chain repacking. Nucleic Acids Res. 2013;41(1):384\u20138.","journal-title":"Nucleic Acids Res"},{"issue":"2","key":"1988_CR27","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1093\/nar\/gkp322","volume":"37","author":"P Benkert","year":"2009","unstructured":"Benkert P, K\u00fcnzli M, Schwede T. QMEAN server for protein model quality estimation. Nucleic Acids Res. 2009;37(2):510\u20134.","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"1988_CR28","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1007\/s12539-020-00382-8","volume":"12","author":"T Hashempour","year":"2020","unstructured":"Hashempour T, Dehghani B, Musavi Z, Moayedi J, Hasanshahi Z, Sarvari J, et al. Impact of IL28 genotypes and modeling the interactions of HCV core protein on treatment of hepatitis C. Interdiscip Sci Comput Life Sci. 2020;12(4):424\u201337.","journal-title":"Interdiscip Sci Comput Life Sci"},{"issue":"8","key":"1988_CR29","doi-asserted-by":"publisher","first-page":"e40959","DOI":"10.5812\/hepatmon.guideline","volume":"16","author":"SM Alavian","year":"2016","unstructured":"Alavian SM, Hajarizadeh B, Bagheri Lankarani K, Sharafi H, Ebrahimi Daryani N, Merat S, et al. Recommendations for the clinical management of hepatitis C in Iran: a consensus-based national guideline. Hepat Mon. 2016;16(8):e40959.","journal-title":"Hepat Mon"},{"issue":"6","key":"1988_CR30","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1002\/jmv.25048","volume":"90","author":"M Grandal","year":"2018","unstructured":"Grandal M, Pernas B, Tabernilla A, Mari\u00f1o A, \u00c1lvarez H, Valcarce N, et al. Prevalence of NS5A resistance associated substitutions in patients with hepatitis C virus genotypes 1a and 3: impact on current therapeutic strategies. J Med Virol. 2018;90(6):1094\u20138.","journal-title":"J Med Virol"},{"key":"1988_CR31","doi-asserted-by":"publisher","first-page":"2514901","DOI":"10.1155\/2018\/2514901","volume":"2018","author":"F Aldunate","year":"2018","unstructured":"Aldunate F, Echeverr\u00eda N, Chiodi D, L\u00f3pez P, S\u00e1nchez-Cicer\u00f3n A, Fajardo A, et al. Pretreatment hepatitis C virus NS5A\/NS5B resistance-associated substitutions in genotype 1 Uruguayan infected patients. Dis Markers. 2018;2018:2514901.","journal-title":"Dis Markers"},{"issue":"535","key":"1988_CR32","first-page":"1","volume":"10","author":"J Lu","year":"2019","unstructured":"Lu J, Feng Y, Chen L, Zeng Z, Liu X, Cai W, et al. Subtype-specific prevalence of hepatitis C virus NS5A resistance associated substitutions in Mainland China. Front Microbiol. 2019;10(535):1\u201311.","journal-title":"Front Microbiol"},{"issue":"5","key":"1988_CR33","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1016\/j.clinre.2019.01.011","volume":"43","author":"A Ramezani","year":"2019","unstructured":"Ramezani A, Baesi K, Banifazl M, Mohraz M, Khorvash F, Yaran M, et al. Naturally occurring NS5A and NS5B resistant associated substitutions in HCV and HCV\/HIV patients in Iranian population. Clin Res Hepatol Gastroenterol. 2019;43(5):594\u2013602.","journal-title":"Clin Res Hepatol Gastroenterol"},{"issue":"1","key":"1988_CR34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-26862-y","volume":"8","author":"A Bertoli","year":"2018","unstructured":"Bertoli A, Sorbo MC, Aragri M, Lenci I, Teti E, Polilli E, et al. Prevalence of single and multiple natural NS3, NS5A and NS5B resistance-associated substitutions in hepatitis C virus genotypes 1\u20134 in Italy. Sci Rep. 2018;8(1):1\u201311.","journal-title":"Sci Rep"},{"issue":"1","key":"1988_CR35","first-page":"12","volume":"44","author":"M Di Stefano","year":"2021","unstructured":"Di Stefano M, Faleo G, Mohamed AMF, Morella S, Bruno SR, Tundo P, et al. Resistance associated mutations in HCV patients failing DAA treatment. New Microbiol. 2021;44(1):12\u20138.","journal-title":"New Microbiol"},{"issue":"9","key":"1988_CR36","doi-asserted-by":"publisher","first-page":"1832","DOI":"10.3390\/v13091832","volume":"13","author":"M Di Stefano","year":"2021","unstructured":"Di Stefano M, Ismail M, Faleo G, Adem SE, Elamin M, Eltreifi O, et al. Genetic subtypes and natural resistance mutations in HCV genotype 4 infected Saudi Arabian patients. Viruses. 2021;13(9):1832.","journal-title":"Viruses"},{"issue":"23","key":"1988_CR37","doi-asserted-by":"publisher","first-page":"1674","DOI":"10.1128\/AEM.01674-20","volume":"86","author":"J Heffron","year":"2020","unstructured":"Heffron J, Mayer BK. Improved virus isoelectric point estimation by exclusion of known and predicted genome-binding regions. Appl Environ Microbiol. 2020;86(23):1674\u201394.","journal-title":"Appl Environ Microbiol"},{"key":"1988_CR38","doi-asserted-by":"crossref","unstructured":"Li DK, Chung RT. Overview of direct-acting antiviral drugs and drug resistance of hepatitis C virus. M L, editor. New York: Humana Press; 2019. p. 3\u201332.","DOI":"10.1007\/978-1-4939-8976-8_1"},{"issue":"9","key":"1988_CR39","doi-asserted-by":"publisher","first-page":"5018","DOI":"10.3390\/v7092857","volume":"7","author":"L Cuypers","year":"2015","unstructured":"Cuypers L, Li G, Libin P, Piampongsant S, Vandamme A-M, Theys K. Genetic diversity and selective pressure in hepatitis C virus genotypes 1\u20136: significance for direct-acting antiviral treatment and drug resistance. Viruses. 2015;7(9):5018\u201339.","journal-title":"Viruses"},{"issue":"10","key":"1988_CR40","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.4254\/wjh.v7.i10.1377","volume":"7","author":"H-C Li","year":"2015","unstructured":"Li H-C, Lo S-Y. Hepatitis C virus: virology, diagnosis and treatment. World J Hepatol. 2015;7(10):1377\u201389.","journal-title":"World J Hepatol"},{"issue":"5","key":"1988_CR41","doi-asserted-by":"publisher","first-page":"445","DOI":"10.4103\/ijmr.IJMR_1850_16","volume":"147","author":"A Kumar","year":"2018","unstructured":"Kumar A, Rajput MK, Paliwal D, Yadav A, Chhabra R, Singh S. Genotyping & diagnostic methods for hepatitis C virus: a need of low-resource countries. Indian J Med Res. 2018;147(5):445\u201355.","journal-title":"Indian J Med Res"},{"issue":"7","key":"1988_CR42","doi-asserted-by":"publisher","first-page":"1835","DOI":"10.1128\/JCM.00238-16","volume":"54","author":"KS Ku","year":"2016","unstructured":"Ku KS, Chodavarapu RK, Martin R, Miller MD, Mo H, Svarovskaia ES. Sequencing analysis of NS3\/4A, NS5A, and NS5B genes from patients infected with hepatitis c virus genotypes 5 and 6. J Clin Microbiol. 2016;54(7):1835\u201341.","journal-title":"J Clin Microbiol"},{"issue":"2","key":"1988_CR43","doi-asserted-by":"publisher","first-page":"862","DOI":"10.3748\/wjg.v22.i2.862","volume":"22","author":"ZNAS Kouka Saadeldin Abdelwahab","year":"2016","unstructured":"Kouka Saadeldin Abdelwahab ZNAS. Status of hepatitis C virus vaccination: recent update. World J Gastroenterol. 2016;22(2):862\u201373.","journal-title":"World J Gastroenterol"},{"issue":"1","key":"1988_CR44","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3390\/vaccines8010090","volume":"8","author":"JD Duncan","year":"2020","unstructured":"Duncan JD, Urbanowicz RA, Tarr AW, Ball JK. Hepatitis C virus vaccine: challenges and prospects. Vaccines. 2020;8(1):90\u2013113.","journal-title":"Vaccines"},{"issue":"3","key":"1988_CR45","first-page":"214","volume":"20","author":"GR Sharifi-Sirchi","year":"2016","unstructured":"Sharifi-Sirchi GR, Jalali-Javaran M. Selecting appropriate hosts for recombinant proteins production. Hormozgan Med J. 2016;20(3):214\u201322.","journal-title":"Hormozgan Med J"},{"issue":"111","key":"1988_CR46","first-page":"1","volume":"12","author":"MI Anwar","year":"2013","unstructured":"Anwar MI, Iqbal M, Yousef MS, Rahman M. Over-expression and characterization of NS3 and NS5A of hepatitis C virus genotype 3a. Microb Cell Fact. 2013;12(111):1\u201312.","journal-title":"Microb Cell Fact"},{"issue":"3","key":"1988_CR47","first-page":"383","volume":"1","author":"XG Dou","year":"2002","unstructured":"Dou XG, Feng GH, Shi LL, Fields H. Gene expression of NS5a strong antigenic regions of hepatitis C virus in E. coli and detection of their antigenicity. HBPD Int. 2002;1(3):383\u20137.","journal-title":"HBPD Int"},{"issue":"9","key":"1988_CR48","doi-asserted-by":"publisher","first-page":"1733","DOI":"10.1007\/s00705-002-0836-0","volume":"147","author":"M Kalamvoki","year":"2002","unstructured":"Kalamvoki M, Miriagou V, Hadziyannis A, Georgopoulou U, Varaklioti A, Hadziyannis S, et al. Expression of immunoreactive forms of the hepatitis C NS5A protein in E. coli and their use for diagnostic assays. Arch Virol. 2002;147(9):1733\u201345.","journal-title":"Arch Virol"},{"issue":"4","key":"1988_CR49","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.jmii.2012.08.016","volume":"47","author":"M Alaee","year":"2014","unstructured":"Alaee M, Rajabi P, Sharifi Z, Farajollahi MM. Immunoreactivity assessment of hepatitis C virus NS3 protease and NS5A proteins expressed in TOPO cloning system. J Microbiol Immunol Infect. 2014;47(4):282\u201391.","journal-title":"J Microbiol Immunol Infect"},{"issue":"43","key":"1988_CR50","doi-asserted-by":"publisher","first-page":"36417","DOI":"10.1074\/jbc.M508175200","volume":"280","author":"L Huang","year":"2005","unstructured":"Huang L, Hwang J, Sharma SD, Hargittai MR, Chen Y, Arnold JJ, et al. Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein. J Biol Chem. 2005;280(43):36417\u201328.","journal-title":"J Biol Chem"},{"issue":"13","key":"1988_CR51","doi-asserted-by":"publisher","first-page":"6095","DOI":"10.1128\/JVI.75.13.6095-6106.2001","volume":"75","author":"SJ Polyak","year":"2001","unstructured":"Polyak SJ, Khabar KS, Paschal DM, Ezelle HJ, Duverlie G, Barber GN, et al. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol. 2001;75(13):6095\u2013106.","journal-title":"J Virol"},{"issue":"7","key":"1988_CR52","doi-asserted-by":"publisher","first-page":"3332","DOI":"10.1128\/JVI.80.7.3332-3340.2006","volume":"80","author":"T Shimakami","year":"2006","unstructured":"Shimakami T, Honda M, Kusakawa T, Murata T, Shimotohno K, Kaneko S, et al. Effect of hepatitis C virus (HCV) NS5B-nucleolin interaction on HCV replication with HCV subgenomic replicon. J Virol. 2006;80(7):3332\u201340.","journal-title":"J Virol"},{"issue":"10","key":"1988_CR53","doi-asserted-by":"publisher","first-page":"5288","DOI":"10.1128\/JVI.78.10.5288-5298.2004","volume":"78","author":"P-Y Goh","year":"2004","unstructured":"Goh P-Y, Tan Y-J, Lim SP, Tan Y, Lim SG, Fuller-Pace F, et al. Cellular RNA helicase p68 relocalization and interaction with the hepatitis C virus (HCV) NS5B protein and the potential role of p68 in HCV RNA replication. J Virol. 2004;78(10):5288\u201398.","journal-title":"J Virol"},{"issue":"3","key":"1988_CR54","first-page":"312","volume":"98","author":"V Kumar","year":"2010","unstructured":"Kumar V, Das S, Jameel S. The biology and pathogenesis of hepatitis viruses. Curr Sci. 2010;98(3):312\u201325.","journal-title":"Curr Sci"},{"issue":"47","key":"1988_CR55","doi-asserted-by":"publisher","first-page":"8929","DOI":"10.3748\/wjg.v19.i47.8929","volume":"19","author":"J Hundt","year":"2013","unstructured":"Hundt J, Li Z, Liu Q. Post-translational modifications of hepatitis C viral proteins and their biological significance. World J Gastroenterol. 2013;19(47):8929\u201339.","journal-title":"World J Gastroenterol"},{"issue":"2","key":"1988_CR56","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/nrc3449","volume":"13","author":"A Arzumanyan","year":"2013","unstructured":"Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV-and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 2013;13(2):123\u201335.","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"1988_CR57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.virol.2007.01.042","volume":"364","author":"Y Huang","year":"2007","unstructured":"Huang Y, Staschke K, De Francesco R, Tan S-L. Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication? Virology. 2007;364(1):1\u20139.","journal-title":"Virology"},{"issue":"8","key":"1988_CR58","doi-asserted-by":"publisher","first-page":"3918","DOI":"10.1074\/jbc.M115.675413","volume":"291","author":"WM Chong","year":"2016","unstructured":"Chong WM, Hsu S-C, Kao W-T, Lo C-W, Lee K-Y, Shao J-S, et al. Phosphoproteomics identified an NS5A phosphorylation site involved in hepatitis C virus replication. J Biol Chem. 2016;291(8):3918\u201331.","journal-title":"J Biol Chem"},{"issue":"13","key":"1988_CR59","doi-asserted-by":"publisher","first-page":"7541","DOI":"10.1128\/JVI.03170-13","volume":"88","author":"T Masaki","year":"2014","unstructured":"Masaki T, Matsunaga S, Takahashi H, Nakashima K, Kimura Y, Ito M, et al. Involvement of hepatitis C virus NS5A hyperphosphorylation mediated by casein kinase I-\u03b1 in infectious virus production. J Virol. 2014;88(13):7541\u201355.","journal-title":"J Virol"},{"key":"1988_CR60","doi-asserted-by":"crossref","unstructured":"Goonawardane N, Yin C, Harris M. A pivotal role of serine 225 phosphorylation in the function of hepatitis C virus NS5A revealed with the application of a phosphopeptide antiserum and super-resolution microscopy. BioRxiv. 2018:387407.","DOI":"10.1101\/387407"},{"issue":"19","key":"1988_CR61","doi-asserted-by":"publisher","first-page":"11240","DOI":"10.1128\/JVI.01826-14","volume":"88","author":"S-H Han","year":"2014","unstructured":"Han S-H, Kim S-J, Kim E-J, Kim T-E, Moon J-S, Kim G-W, et al. Phosphorylation of hepatitis C virus RNA polymerases ser29 and ser42 by protein kinase C-related kinase 2 regulates viral RNA replication. J Virol. 2014;88(19):11240\u201352.","journal-title":"J Virol"},{"issue":"13","key":"1988_CR62","doi-asserted-by":"publisher","first-page":"11290","DOI":"10.1074\/jbc.M110.194472","volume":"286","author":"Y-S Lim","year":"2011","unstructured":"Lim Y-S, Hwang SB. Hepatitis C virus NS5A protein interacts with phosphatidylinositol 4-kinase type III\u03b1 and regulates viral propagation. J Biol Chem. 2011;286(13):11290\u20138.","journal-title":"J Biol Chem"},{"issue":"21","key":"1988_CR63","doi-asserted-by":"publisher","first-page":"13473","DOI":"10.1128\/JVI.79.21.13473-13482.2005","volume":"79","author":"I Hamamoto","year":"2005","unstructured":"Hamamoto I, Nishimura Y, Okamoto T, Aizaki H, Liu M, Mori Y, et al. Human VAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B. J Virol. 2005;79(21):13473\u201382.","journal-title":"J Virol"},{"key":"1988_CR64","doi-asserted-by":"crossref","unstructured":"Yamasaki LH, Arcuri HA, Jardim ACG, Bittar C, de Carvalho-Mello IMV, Rahal P. New insights regarding HCV-NS5A structure\/function and indication of genotypic differences. Virology J. 2012;9(14).","DOI":"10.1186\/1743-422X-9-14"},{"issue":"3","key":"1988_CR65","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1128\/JVI.01219-07","volume":"82","author":"J Graff","year":"2008","unstructured":"Graff J, Zhou Y-H, Torian U, Nguyen H, Claire MS, Yu C, et al. Mutations within potential glycosylation sites in the capsid protein of hepatitis E virus prevent the formation of infectious virus particles. J Virol. 2008;82(3):1185\u201394.","journal-title":"J Virol"},{"issue":"3","key":"1988_CR66","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1091\/mbc.5.3.253","volume":"5","author":"A Helenius","year":"1994","unstructured":"Helenius A. How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum. Mol Biol Cell. 1994;5(3):253\u201365.","journal-title":"Mol Biol Cell"},{"issue":"171","key":"1988_CR67","first-page":"1","volume":"11","author":"S Kanwal","year":"2014","unstructured":"Kanwal S, Mahmood T. Occurrence of genetic modifications in core, 5\u2032 UTR and NS5b of HCV associated with viral response to treatment. Virology J. 2014;11(171):1\u201320.","journal-title":"Virology J"},{"issue":"5","key":"1988_CR68","doi-asserted-by":"publisher","first-page":"802","DOI":"10.2478\/s11535-011-0050-8","volume":"6","author":"D Vigerust","year":"2011","unstructured":"Vigerust D. Protein glycosylation in infectious disease pathobiology and treatment. Open Life Sci. 2011;6(5):802\u201316.","journal-title":"Open Life Sci"},{"issue":"7040","key":"1988_CR69","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1038\/nature03580","volume":"435","author":"TL Tellinghuisen","year":"2005","unstructured":"Tellinghuisen TL, Marcotrigiano J, Rice CM. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature. 2005;435(7040):374\u20139.","journal-title":"Nature"},{"issue":"36","key":"1988_CR70","doi-asserted-by":"publisher","first-page":"30861","DOI":"10.1074\/jbc.M112.376822","volume":"287","author":"PJ Lim","year":"2012","unstructured":"Lim PJ, Chatterji U, Cordek D, Sharma SD, Garcia-Rivera JA, Cameron CE, et al. Correlation between NS5A dimerization and hepatitis C virus replication. J Biol Chem. 2012;287(36):30861\u201373.","journal-title":"J Biol Chem"},{"issue":"10","key":"1988_CR71","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1007\/s00216-017-0772-1","volume":"410","author":"JC Lakbub","year":"2018","unstructured":"Lakbub JC, Shipman JT, Desaire H. Recent mass spectrometry-based techniques and considerations for disulfide bond characterization in proteins. Anal Bioanal Chem. 2018;410(10):2467\u201384.","journal-title":"Anal Bioanal Chem"},{"issue":"1","key":"1988_CR72","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-34254-5","volume":"8","author":"A Ikram","year":"2018","unstructured":"Ikram A, Zaheer T, Awan FM, Obaid A, Naz A, Hanif R, et al. Exploring NS3\/4A, NS5A and NS5B proteins to design conserved subunit multi-epitope vaccine against HCV utilizing immunoinformatics approaches. Sci Rep. 2018;8(1):1\u201314.","journal-title":"Sci Rep"},{"issue":"3","key":"1988_CR73","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.4049\/jimmunol.1201497","volume":"190","author":"F Holmstr\u00f6m","year":"2013","unstructured":"Holmstr\u00f6m F, Pasetto A, N\u00e4hr V, Brass A, Kriegs M, Hildt E, et al. A synthetic codon-optimized hepatitis C virus nonstructural 5A DNA vaccine primes polyfunctional CD8+ T cell responses in wild-type and NS5A-transgenic mice. J Immunol. 2013;190(3):1113\u201324.","journal-title":"J Immunol"},{"issue":"8","key":"1988_CR74","doi-asserted-by":"publisher","first-page":"2357","DOI":"10.4161\/hv.29590","volume":"10","author":"B Latimer","year":"2014","unstructured":"Latimer B, Toporovski R, Yan J, Pankhong P, Morrow MP, Khan AS, et al. Strong HCV NS3\/4a, NS4b, NS5a, NS5b-specific cellular immune responses induced in Rhesus macaques by a novel HCV genotype 1a\/1b consensus DNA vaccine. Hum Vaccin Immunother. 2014;10(8):2357\u201365.","journal-title":"Hum Vaccin Immunother"},{"issue":"12","key":"1988_CR75","doi-asserted-by":"publisher","first-page":"e52165","DOI":"10.1371\/journal.pone.0052165","volume":"7","author":"KA Lang Kuhs","year":"2012","unstructured":"Lang Kuhs KA, Toporovski R, Yan J, Ginsberg AA, Shedlock DJ, Weiner DB. Induction of intrahepatic HCV NS4B, NS5A and NS5B-specific cellular immune responses following peripheral immunization. PLoS ONE. 2012;7(12):e52165.","journal-title":"PLoS ONE"},{"issue":"1","key":"1988_CR76","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1186\/s12879-019-4571-5","volume":"19","author":"RM Dawood","year":"2019","unstructured":"Dawood RM, Moustafa RI, Abdelhafez TH, El-Shenawy R, El-Abd Y, Bader El Din NG, et al. A multiepitope peptide vaccine against HCV stimulates neutralizing humoral and persistent cellular responses in mice. BMC Infect Dis. 2019;19(1):932\u201343.","journal-title":"BMC Infect Dis"},{"issue":"26","key":"1988_CR77","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1007\/s10989-019-09957-6","volume":"2020","author":"T Hashempour","year":"2020","unstructured":"Hashempour T, Dehghani B, Mousavi Z, Yahaghi M, Hasanshahi Z, Moayedi J, et al. Evaluating drug resistant mutations to HCV NS3 protease inhibitors in Iranian Na\u00efve patients. Int J Pept Res Ther. 2020;2020(26):1699\u2013710.","journal-title":"Int J Pept Res Ther"},{"issue":"2","key":"1988_CR78","doi-asserted-by":"publisher","first-page":"154","DOI":"10.2174\/1570164617666190822103329","volume":"17","author":"M Zahra","year":"2020","unstructured":"Zahra M, Tayebeh H, Javad M, Behzad D, Farzaneh G, Mehrdad H, et al. Antibody development to HCV alternate reading frame protein in liver transplant candidate and its computational analysis. Curr Proteom. 2020;17(2):154\u201370.","journal-title":"Curr Proteom"},{"issue":"2","key":"1988_CR79","doi-asserted-by":"publisher","first-page":"107","DOI":"10.2174\/1570164616666190626151949","volume":"17","author":"D Behzad","year":"2020","unstructured":"Behzad D, Tayebeh H, Zahra H. Interaction of human herpesvirus 8 viral interleukin-6 with human interleukin-6 receptor using in silico approach: the potential role in HHV-8 pathogenesis. Curr Proteom. 2020;17(2):107\u201316.","journal-title":"Curr Proteom"},{"key":"1988_CR80","doi-asserted-by":"publisher","first-page":"104266","DOI":"10.1016\/j.meegid.2020.104266","volume":"81","author":"D Dong","year":"2020","unstructured":"Dong D, Zhu Y, Aili Z, Chen Z, Ding J. Bioinformatics analysis of HPV-68 E6 and E7 oncoproteins for designing a therapeutic epitope vaccine against HPV infection. Infect Genet Evol. 2020;81:104266.","journal-title":"Infect Genet Evol"},{"issue":"1","key":"1988_CR81","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1007\/s10989-019-09838-y","volume":"26","author":"B Dehghani","year":"2020","unstructured":"Dehghani B, Hashempour T, Hasanshahi Z, Moayedi J. Bioinformatics analysis of domain 1 of HCV-core protein: Iran. Int J Pept Res Ther. 2020;26(1):303\u201320.","journal-title":"Int J Pept Res Ther"}],"container-title":["BMC Gastroenterology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12876-021-01988-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12876-021-01988-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12876-021-01988-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,29]],"date-time":"2022-10-29T15:04:24Z","timestamp":1667055864000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcgastroenterol.biomedcentral.com\/articles\/10.1186\/s12876-021-01988-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,24]]},"references-count":81,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["1988"],"URL":"https:\/\/doi.org\/10.1186\/s12876-021-01988-y","relation":{},"ISSN":["1471-230X"],"issn-type":[{"value":"1471-230X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,24]]},"assertion":[{"value":"18 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All clinical investigations were conducted according to the\u00a0declaration of Helsinki\u00a0principles. Informed consent was obtained from all subjects and the patients\u2019 code was used to protect the patients\u2019 privacy. This study was approved by the local Ethics Committee of Shiraz University of Medical Sciences, Shiraz, Iran. All methods were carried out in accordance with relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"443"}}