{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T15:58:40Z","timestamp":1777651120358,"version":"3.51.4"},"reference-count":51,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2019,12,1]],"date-time":"2019-12-01T00:00:00Z","timestamp":1575158400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Virus Research"],"published-print":{"date-parts":[[2019,12]]},"DOI":"10.1016\/j.virusres.2019.197778","type":"journal-article","created":{"date-parts":[[2019,10,13]],"date-time":"2019-10-13T09:55:55Z","timestamp":1570960555000},"page":"197778","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":9,"special_numbering":"C","title":["A novel molecular mechanism to explain mutations of the HCV protease associated with resistance against covalently bound inhibitors"],"prefix":"10.1016","volume":"274","author":[{"given":"Leonardo","family":"Nazario de Moraes","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rejane Maria","family":"Tommasini Grotto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guilherme","family":"Targino Valente","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heloisa","family":"de Carvalho Sampaio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo Jos\u00e9","family":"Magro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauana","family":"Foga\u00e7a","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan Rodrigo","family":"Wolf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Perahia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Faria Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Plana Sim\u00f5es","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.virusres.2019.197778_bib0005","first-page":"294","article-title":"Resistance pattern of ciprofloxacin against different pathogens","volume":"25","author":"Ali","year":"2010","journal-title":"Oman Med. J."},{"key":"10.1016\/j.virusres.2019.197778_bib0010","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1021\/ml9000276","article-title":"Discovery of Narlaprevir (SCH 900518): a potent, second generation HCV NS3 serine protease inhibitor","volume":"1","author":"Arasappan","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"10.1016\/j.virusres.2019.197778_bib0015","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1002\/med.21554","article-title":"Evolution of efficacious pangenotypic hepatitis C virus therapies","volume":"39","author":"Ashraf","year":"2019","journal-title":"Med. Res. Rev."},{"key":"10.1016\/j.virusres.2019.197778_bib0020","unstructured":"Boceprevir | C27H45N5O5 | ChemSpider, (2019). http:\/\/www.chemspider.com\/Chemical-Structure.8499830.html?rid=804b888d-f5d3-4873-9eaa-cccda664f353 (n.d.) (Accessed 16 November 2017)."},{"key":"10.1016\/j.virusres.2019.197778_bib0025","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1093\/infdis\/jiy401","article-title":"Identification of a novel hepatitis C virus genotype from Punjab, India: expanding classification of hepatitis C virus into 8 genotypes","volume":"218","author":"Borgia","year":"2018","journal-title":"J. Infect. Dis."},{"key":"10.1016\/j.virusres.2019.197778_bib0030","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: the biomolecular simulation program","volume":"30","author":"Brooks","year":"2009","journal-title":"J. Comput. Chem."},{"key":"10.1016\/j.virusres.2019.197778_bib0035","series-title":"Electrochemical Oxidation of Sulfamethazine on a Glassy Carbon Electrode Modified with Graphene and Gold Nanoparticles","author":"Cesarino","year":"2016"},{"key":"10.1016\/j.virusres.2019.197778_bib0040","doi-asserted-by":"crossref","unstructured":"V.C. Clark, J.A. Peter, D.R. Nelson, New therapeutic strategies in HCV: second-generation protease inhibitors, Liver Int.. 33 (n.d.) 80\u201384. doi:10.1111\/liv.12061.","DOI":"10.1111\/liv.12061"},{"key":"10.1016\/j.virusres.2019.197778_bib0045","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1002\/jmv.24527","article-title":"Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals","volume":"88","author":"Coppola","year":"2016","journal-title":"J. Med. Virol."},{"key":"10.1016\/j.virusres.2019.197778_bib0050","first-page":"15","article-title":"Exploring resistance pathways for first-generation NS3\/4A protease inhibitors boceprevir and telaprevir using Bayesian network learning","volume":"53","author":"Cuypers","year":"2017","journal-title":"Infect. Genet. Evol. J. Mol. Epidemiol. Evol. Genet. Infect. Dis."},{"key":"10.1016\/j.virusres.2019.197778_bib0055","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1093\/bioinformatics\/btq429","article-title":"Datamonkey 2010: a suite of phylogenetic analysis tools for evolutionary biology","volume":"26","author":"Delport","year":"2010","journal-title":"Bioinformatics"},{"key":"10.1016\/j.virusres.2019.197778_bib0060","doi-asserted-by":"crossref","first-page":"W665","DOI":"10.1093\/nar\/gkh381","article-title":"PDB2PQR: an automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations","volume":"32","author":"Dolinsky","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.virusres.2019.197778_bib0065","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jelechem.2017.12.054","article-title":"Reduced graphene oxide modified with silver nanoparticles for the electrochemical detection of estriol","volume":"809","author":"Donini","year":"2018","journal-title":"J. Electroanal. Chem."},{"key":"10.1016\/j.virusres.2019.197778_bib0070","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/molbev\/mss075","article-title":"Bayesian Phylogenetics with BEAUti and the BEAST 1.7","volume":"29","author":"Drummond","year":"2012","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.virusres.2019.197778_bib0075","doi-asserted-by":"crossref","first-page":"1792","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.virusres.2019.197778_bib0080","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/0022-2836(73)90103-4","article-title":"The charge relay system in chymotrypsin and chymotrypsinogen","volume":"74","author":"Fersht","year":"1973","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.virusres.2019.197778_bib0085","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1006\/jmbi.2001.4767","article-title":"Structure, dynamics and electrostatics of the active site of glutaredoxin 3 from Escherichia coli: comparison with functionally related proteins","volume":"310","author":"Foloppe","year":"2001","journal-title":"J. Mol. Biol."},{"key":"10.1016\/j.virusres.2019.197778_bib0090","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.virusres.2007.10.003","article-title":"A wide range of NS3\/4A protease catalytic efficiencies in HCV-infected individuals","volume":"131","author":"Franco","year":"2008","journal-title":"Virus Res."},{"key":"10.1016\/j.virusres.2019.197778_bib0095","series-title":"Gaussian 16, Wallingford, CT","author":"Frisch","year":"2016"},{"key":"10.1016\/j.virusres.2019.197778_bib0100","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1093\/molbev\/msy088","article-title":"Neutral theory and rapidly evolving viral pathogens","volume":"35","author":"Frost","year":"2018","journal-title":"Mol. Biol. Evol."},{"key":"10.1016\/j.virusres.2019.197778_bib0105","doi-asserted-by":"crossref","unstructured":"E. Gonz\u00e1lez\u2010Colominas, T. Broquetas, A. Retamero, M. Garc\u00eda\u2010Retortillo, N. Ca\u00f1ete, S. Coll, R. Pellicer, M.D. Gim\u00e9nez, B. Cabrero, F. Bory, H. Knobel, E. Salas, R. Sol\u00e0, J.A. Carri\u00f3n, Drug\u2013drug interactions of telaprevir and boceprevir in HCV-monoinfected and HIV\/HCV-coinfected patients can modify the adherence, Liver Int.. 35 (n.d.) 1557\u20131565. doi:https:\/\/doi.org\/10.1111\/liv.12729.","DOI":"10.1111\/liv.12729"},{"key":"10.1016\/j.virusres.2019.197778_bib0110","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.jhep.2011.01.011","article-title":"Hepatitis C virus resistance to protease inhibitors","volume":"55","author":"Halfon","year":"2011","journal-title":"J. Hepatol."},{"key":"10.1016\/j.virusres.2019.197778_bib0115","series-title":"Data Mining: Concepts and Techniques","author":"Han","year":"2011"},{"key":"10.1016\/j.virusres.2019.197778_bib0120","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1021\/cr000033x","article-title":"Serine protease mechanism and specificity","volume":"102","author":"Hedstrom","year":"2002","journal-title":"Chem. Rev."},{"key":"10.1016\/j.virusres.2019.197778_bib0125","first-page":"22","article-title":"The discovery and development of boceprevir: a novel, first-generation inhibitor of the hepatitis C virus NS3\/4A serine protease","volume":"1","author":"Howe","year":"2013","journal-title":"J. Clin. Transl. Hepatol."},{"key":"10.1016\/j.virusres.2019.197778_bib0130","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1093\/bioinformatics\/btq003","article-title":"CD-HIT Suite: a web server for clustering and comparing biological sequences","volume":"26","author":"Huang","year":"2010","journal-title":"Bioinforma. Oxf. Engl."},{"key":"10.1016\/j.virusres.2019.197778_bib0135","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1002\/hep.24172","article-title":"Genotype differences in susceptibility and resistance development of hepatitis C virus to protease inhibitors telaprevir (VX-950) and danoprevir (ITMN-191)","volume":"53","author":"Imhof","year":"2011","journal-title":"Hepatol. Baltim. Md."},{"key":"10.1016\/j.virusres.2019.197778_bib0140","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.1128\/AAC.01578-13","article-title":"In vitro phenotypic characterization of hepatitis C virus NS3 protease variants observed in clinical studies of telaprevir","volume":"57","author":"Jiang","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.virusres.2019.197778_bib0145","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0092-8674(00)81351-3","article-title":"Crystal structure of the hepatitis C virus NS3 protease domain complexed with a synthetic NS4A cofactor peptide","volume":"87","author":"Kim","year":"1996","journal-title":"Cell"},{"key":"10.1016\/j.virusres.2019.197778_bib0150","doi-asserted-by":"crossref","first-page":"e104425","DOI":"10.1371\/journal.pone.0104425","article-title":"Comparative molecular dynamics simulation of hepatitis C virus NS3\/4A protease (genotypes 1b, 3a and 4a) predicts conformational instability of the catalytic triad in drug resistant strains","volume":"9","author":"Kramer","year":"2014","journal-title":"PLoS One"},{"key":"10.1016\/j.virusres.2019.197778_bib0155","doi-asserted-by":"crossref","first-page":"11940","DOI":"10.1021\/bi980278s","article-title":"Correlations of the basicity of his 57 with transition state analogue binding, substrate reactivity, and the strength of the low-barrier hydrogen bond in chymotrypsin","volume":"37","author":"Lin","year":"1998","journal-title":"Biochemistry"},{"key":"10.1016\/j.virusres.2019.197778_bib0160","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1002\/hep.27934","article-title":"Hepatitis C virus drug resistance-associated substitutions: state of the art summary","volume":"62","author":"Lontok","year":"2015","journal-title":"Hepatol. Baltim. Md."},{"key":"10.1016\/j.virusres.2019.197778_bib0165","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1128\/AAC.50.3.1013-1020.2006","article-title":"SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells","volume":"50","author":"Malcolm","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"10.1016\/j.virusres.2019.197778_bib0170","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1021\/ci400605a","article-title":"Key binding and susceptibility of NS3\/4A serine protease inhibitors against hepatitis C virus","volume":"54","author":"Meeprasert","year":"2014","journal-title":"J. Chem. Inf. Model."},{"key":"10.1016\/j.virusres.2019.197778_bib0175","first-page":"1","article-title":"Creating the CIPRES Science Gateway for inference of large phylogenetic trees","author":"Miller","year":"2010","journal-title":"2010 Gatew. Comput. Environ. Workshop GCE"},{"key":"10.1016\/j.virusres.2019.197778_bib0180","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1097\/MOT.0b013e32835a2bac","article-title":"Hepatitis C and renal transplantation","volume":"17","author":"Morales","year":"2012","journal-title":"Curr. Opin. Organ Transplant."},{"key":"10.1016\/j.virusres.2019.197778_bib0185","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/hep.20032","article-title":"Structural biology of hepatitis C virus","volume":"39","author":"Penin","year":"2004","journal-title":"Hepatology"},{"key":"10.1016\/j.virusres.2019.197778_bib0190","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1021\/jm060173k","volume":"50","author":"Prongay","year":"2007","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.virusres.2019.197778_bib0195","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.1093\/nar\/gkp251","article-title":"Identification of HCV protease inhibitor resistance mutations by selection pressure-based method","volume":"37","author":"Qiu","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"10.1016\/j.virusres.2019.197778_bib0200","doi-asserted-by":"crossref","first-page":"22725","DOI":"10.1074\/jbc.R110.125294","article-title":"Hepatitis C virus non-structural protein 3 (HCV NS3): a multifunctional antiviral target","volume":"285","author":"Raney","year":"2010","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.virusres.2019.197778_bib0205","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1080\/07391102.2013.800001","article-title":"A 3D structural model and dynamics of hepatitis C virus NS3\/4A protease (genotype 4a, strain ED43) suggest conformational instability of the catalytic triad: implications in catalysis and drug resistivity","volume":"32","author":"Rimmert","year":"2014","journal-title":"J. Biomol. Struct. Dyn."},{"key":"10.1016\/j.virusres.2019.197778_bib0210","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1007\/s00018-016-2299-6","article-title":"Mechanisms of viral mutation","volume":"73","author":"Sanju\u00e1n","year":"2016","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"10.1016\/j.virusres.2019.197778_bib0215","doi-asserted-by":"crossref","DOI":"10.1186\/s12859-016-1114-6","article-title":"Automated prediction of HIV drug resistance from genotype data","volume":"17","author":"Shen","year":"2016","journal-title":"BMC Bioinformatics"},{"key":"10.1016\/j.virusres.2019.197778_bib0220","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0040029","article-title":"Probing of exosites leads to novel inhibitor scaffolds of HCV NS3\/4A proteinase","volume":"7","author":"Shiryaev","year":"2012","journal-title":"PLoS One"},{"key":"10.1016\/j.virusres.2019.197778_bib0225","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/978-1-62703-646-7_6","article-title":"Clustal Omega, accurate alignment of very large numbers of sequences","volume":"1079","author":"Sievers","year":"2014","journal-title":"Methods Mol. Biol. Clifton NJ."},{"key":"10.1016\/j.virusres.2019.197778_bib0230","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1002\/hep.20819","article-title":"Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes","volume":"42","author":"Simmonds","year":"2005","journal-title":"Hepatol. Baltim. Md."},{"key":"10.1016\/j.virusres.2019.197778_bib0235","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/hep.26744","article-title":"Expanded classification of hepatitis C virus into 7 genotypes and 67 subtypes: updated criteria and genotype assignment web resource","volume":"59","author":"Smith","year":"2014","journal-title":"Hepatol. Baltim. Md."},{"key":"10.1016\/j.virusres.2019.197778_bib0240","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1093\/bioinformatics\/btu033","article-title":"RAxML version 8: a tool for phylogenetic analysis and post-analysis of large phylogenies","volume":"30","author":"Stamatakis","year":"2014","journal-title":"Bioinformatics"},{"key":"10.1016\/j.virusres.2019.197778_bib0245","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM general force field: a force field for drug-like molecules compatible with the CHARMM all-atom additive biological force fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. Comput. Chem."},{"key":"10.1016\/j.virusres.2019.197778_bib0250","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.tips.2012.03.012","article-title":"Discovery of boceprevir, a direct-acting NS3\/4A protease inhibitor for treatment of chronic hepatitis C infections","volume":"33","author":"Venkatraman","year":"2012","journal-title":"Trends Pharmacol. Sci."},{"key":"10.1016\/j.virusres.2019.197778_bib0255","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.rce.2017.07.006","article-title":"Treatment of hepatitisC virus with direct-acting antivirals: practical aspects and current situation","volume":"218","author":"Vivancos","year":"2018","journal-title":"Rev. Clin. Esp."}],"container-title":["Virus Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S016817021930526X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S016817021930526X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T14:09:01Z","timestamp":1759154941000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S016817021930526X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12]]},"references-count":51,"alternative-id":["S016817021930526X"],"URL":"https:\/\/doi.org\/10.1016\/j.virusres.2019.197778","relation":{},"ISSN":["0168-1702"],"issn-type":[{"value":"0168-1702","type":"print"}],"subject":[],"published":{"date-parts":[[2019,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"A novel molecular mechanism to explain mutations of the HCV protease associated with resistance against covalently bound inhibitors","name":"articletitle","label":"Article Title"},{"value":"Virus Research","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.virusres.2019.197778","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 Elsevier B.V. All rights reserved.","name":"copyright","label":"Copyright"}],"article-number":"197778"}}