{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T21:37:02Z","timestamp":1791841022026,"version":"4.3.4"},"reference-count":256,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007219","name":"Natural Science Foundation of Shanghai","doi-asserted-by":"publisher","award":["19ZR1469000"],"award-info":[{"award-number":["19ZR1469000"]}],"id":[{"id":"10.13039\/100007219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2016YFD0500404"],"award-info":[{"award-number":["2016YFD0500404"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Central Public-interest Scientific Institution Basal Research Fund","award":["Y2020PT40"],"award-info":[{"award-number":["Y2020PT40"]}]},{"name":"Shanghai Science and Technology Development Funds","award":["17391901600"],"award-info":[{"award-number":["17391901600"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Flaviviruses are known to cause a variety of diseases in humans in different parts of the world. There are very limited numbers of antivirals to combat flavivirus infection, and therefore new drug targets must be explored. The flavivirus NS2B-NS3 proteases are responsible for the cleavage of the flavivirus polyprotein, which is necessary for productive viral infection and for causing clinical infections; therefore, they are a promising drug target for devising novel drugs against different flaviviruses. This review highlights the structural details of the NS2B-NS3 proteases of different flaviviruses, and also describes potential antiviral drugs that can interfere with the viral protease activity, as determined by various studies. Moreover, optimized in vitro reaction conditions for studying the NS2B-NS3 proteases of different flaviviruses may vary and have been incorporated in this review. The increasing availability of the in silico and crystallographic\/structural details of flavivirus NS2B-NS3 proteases in free and drug-bound states can pave the path for the development of promising antiflavivirus drugs to be used in clinics. However, there is a paucity of information available on using animal cells and models for studying flavivirus NS2B-NS3 proteases, as well as on the testing of the antiviral drug efficacy against NS2B-NS3 proteases. Therefore, on the basis of recent studies, an effort has also been made to propose potential cellular and animal models for the study of flavivirus NS2B-NS3 proteases for the purposes of exploring flavivirus pathogenesis and for testing the efficacy of possible drugs targets, in vitro and in vivo.<\/jats:p>","DOI":"10.3390\/v14010044","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:31:27Z","timestamp":1640745087000},"page":"44","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1919-3653","authenticated-orcid":false,"given":"Abdul","family":"Wahaab","sequence":"first","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahar E","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Sub Campus Toba Tek Singh, University of Agriculture, Faisalabad 36050, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muddassar","family":"Hameed","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China"},{"name":"Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Polytechnic Institute, State University, Fralin Life Sciences Building, 360 W Campus Blacksburg, Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6966-9314","authenticated-orcid":false,"given":"Nigel J.","family":"Stevenson","sequence":"additional","affiliation":[{"name":"Royal College of Surgeons in Ireland, Medical University of Bahrain, Busaiteen, Adliya 15503, Bahrain"},{"name":"Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02 R590 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4762-1635","authenticated-orcid":false,"given":"Muhammad Naveed","family":"Anwar","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3246-6273","authenticated-orcid":false,"given":"Jianchao","family":"Wei","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-0817","authenticated-orcid":false,"given":"Yafeng","family":"Qiu","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Ma","sequence":"additional","affiliation":[{"name":"Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, Shanghai 200241, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1159\/000149642","article-title":"Flaviviridae","volume":"24","author":"Westaway","year":"1985","journal-title":"Intervirology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-3527(03)59001-7","article-title":"Taxonomy of the virus family Flaviviridae","volume":"59","author":"Calisher","year":"2003","journal-title":"Adv. Virus Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.virusres.2006.01.021","article-title":"Functional characterization of the NS2B\/NS3 protease complex from seven viruses belonging to different groups inside the genus Flavivirus","volume":"120","author":"Bessaud","year":"2006","journal-title":"Virus Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/nrmicro1067","article-title":"A structural perspective of the flavivirus life cycle","volume":"3","author":"Mukhopadhyay","year":"2005","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1089\/vbz.2019.2467","article-title":"Infection of Western Gray Kangaroos (Macropus fuliginosus) with Australian Arboviruses Associated with Human Infection","volume":"20","author":"Gyawali","year":"2020","journal-title":"Vector-Borne Zoonotic Dis."},{"key":"ref_6","first-page":"604","article-title":"The neurovirulence of flaviviruses in crab-eating monkeys (Macaca fascicularis)","volume":"17","author":"Angsubhakorn","year":"1986","journal-title":"S. Asian J. Trop. Med. Public Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1186\/s13071-019-3732-0","article-title":"Sylvatic cycles of arboviruses in non-human primates","volume":"12","author":"Valentine","year":"2019","journal-title":"Parasites Vectors"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/j.vetmic.2009.08.025","article-title":"Zoonotic mosquito-borne flaviviruses: Worldwide presence of agents with proven pathogenicity and potential candidates of future emerging diseases","volume":"140","author":"Bakonyi","year":"2010","journal-title":"Veter Microbiol."},{"key":"ref_9","first-page":"1660129","article-title":"Urban transmission of mosquito-borne flaviviruses\u2014A review of the risk for humans in Vietnam","volume":"9","author":"Lundkvist","year":"2019","journal-title":"Infect. Ecol. Epidemiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.coviro.2016.11.007","article-title":"Flavivirus transmission focusing on Zika","volume":"22","author":"Vasilakis","year":"2017","journal-title":"Curr. Opin. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virusres.2017.07.011","article-title":"Mosquito-borne and sexual transmission of Zika virus: Recent developments and future directions","volume":"254","author":"Magalhaes","year":"2018","journal-title":"Virus Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5425","DOI":"10.1038\/s41467-018-07896-2","article-title":"Predicting wildlife reservoirs and global vulnerability to zoonotic Flaviviruses","volume":"9","author":"Pandit","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Blahove, M.R., and Carter, J.R. (2021). Flavivirus Persistence in Wildlife Populations. Viruses, 13.","DOI":"10.3390\/v13102099"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/jmedent\/41.5.93","article-title":"Host range specificity of flaviviruses: Correlation with in vitro replication","volume":"44","author":"Kuno","year":"2007","journal-title":"J. Med. Entomol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Mign\u00e9, C., Moutailler, S., and Attoui, H. (2020). Strategies for Assessing Arbovirus Genetic Variability in Vectors and\/or Mammals. Pathogens, 9.","DOI":"10.3390\/pathogens9110915"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"eaax7989","DOI":"10.1126\/sciadv.aax7989","article-title":"Flavivirus induces and antagonizes antiviral RNA interference in both mammals and mosquitoes","volume":"6","author":"Qiu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4833","DOI":"10.1038\/s41598-019-41302-1","article-title":"CX3CR1-CX3CL1-dependent cell-to-cell Japanese encephalitis virus transmission by human microglial cells","volume":"9","author":"Lannes","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hameed, M., Liu, K., Anwar, N., Wahaab, A., Safdar, A., Di, D., Boruah, P., Xu, J., Wang, X., and Li, B. (2019). The emerged genotype I of Japanese encephalitis virus shows an infectivity similar to genotype III in Culex pipiens mosquitoes from China. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007716"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"591478","DOI":"10.3389\/fmicb.2020.591478","article-title":"A Metagenomic Analysis of Mosquito Virome Collected From Different Animal Farms at Yunnan\u2013Myanmar Border of China","volume":"11","author":"Hameed","year":"2021","journal-title":"Front. Microbiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s13365-014-0285-z","article-title":"Flaviviruses, an expanding threat in public health: Focus on dengue, West Nile, and Japanese encephalitis virus","volume":"20","author":"Daep","year":"2014","journal-title":"J. Neurovirol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1128\/JVI.72.1.73-83.1998","article-title":"Phylogeny of the Genus Flavivirus","volume":"72","author":"Kuno","year":"1998","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4731","DOI":"10.1128\/JVI.00002-08","article-title":"Role of Nonstructural Protein NS2A in Flavivirus Assembly","volume":"82","author":"Leung","year":"2008","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1437","DOI":"10.1002\/wrna.1437","article-title":"Organization of the Flavivirus RNA replicase complex","volume":"8","author":"Brand","year":"2017","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1146\/annurev.mi.44.100190.003245","article-title":"Flavivirus Genome Organization, Expression, and Replication","volume":"44","author":"Chambers","year":"1990","journal-title":"Ann. Rev. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3108","DOI":"10.1128\/JVI.73.4.3108-3116.1999","article-title":"The Serine Protease and RNA-Stimulated Nucleoside Triphosphatase and RNA Helicase Functional Domains of Dengue Virus Type 2 NS3 Converge within a Region of 20 Amino Acids","volume":"73","author":"Li","year":"1999","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/S0014-5793(99)01705-6","article-title":"Identification and characterization of the RNA helicase activity of Japanese encephalitis virus NS3 protein","volume":"465","author":"Utama","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4364","DOI":"10.1128\/jvi.64.9.4364-4374.1990","article-title":"In vitro processing of dengue virus type 2 nonstructural proteins NS2A, NS2B, and NS3","volume":"64","author":"Preugschat","year":"1990","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1006\/viro.1993.1587","article-title":"The NS 3 nonstructural protein of flaviviruses contains an RNA triphosphatase activity","volume":"197","author":"Wengler","year":"1993","journal-title":"Virology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/BF01702653","article-title":"Japanese encephalitis virus nonstructural protein NS3 has RNA binding and ATPase activities","volume":"9","author":"Takegami","year":"1995","journal-title":"Virus Genes"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1099\/0022-1317-72-4-851","article-title":"In vitro synthesis of West Nile virus proteins indicates that the amino-terminal segment of the NS3 protein contains the active centre of the protease which cleaves the viral polyprotein after multiple basic amino acids","volume":"72","author":"Wengler","year":"1991","journal-title":"J. General Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1128\/jvi.67.2.989-996.1993","article-title":"RNA-stimulated NTPase activity associated with yellow fever virus NS3 protein expressed in bacteria","volume":"67","author":"Warrener","year":"1993","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wahaab, A., Liu, K., Hameed, M., Anwar, M., Kang, L., Li, C., Ma, X., Wajid, A., Yang, Y., and Khan, U. (2021). Identification of Cleavage Sites Proteolytically Processed by NS2B-NS3 Protease in Polyprotein of Japanese Encephalitis Virus. Pathogens, 10.","DOI":"10.3390\/pathogens10020102"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0166-0934(00)00270-6","article-title":"Expression and purification of enzymatically active recombinant RNA-dependent RNA polymerase (NS5) of the flavivirus Kunjin","volume":"92","author":"Guyatt","year":"2001","journal-title":"J. Virol. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1006\/viro.1996.0067","article-title":"Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity","volume":"216","author":"Tan","year":"1996","journal-title":"Virology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.1093\/emboj\/21.11.2757","article-title":"An RNA cap (nucleoside-2\u2032-O-)-methyltransferase in the flavivirus RNA polymerase NS5: Crystal structure and functional characterization","volume":"21","author":"Egloff","year":"2002","journal-title":"EMBO J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1261\/rna.1609709","article-title":"The flavivirus NS5 protein is a true RNA guanylyltransferase that catalyzes a two-step reaction to form the RNA cap structure","volume":"15","author":"Issur","year":"2009","journal-title":"RNA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8362","DOI":"10.1128\/JVI.00814-06","article-title":"West Nile Virus 5\u2032-Cap Structure Is Formed by Sequential Guanine N-7 and Ribose 2\u2032-O Methylations by Nonstructural Protein 5","volume":"80","author":"Ray","year":"2006","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4881","DOI":"10.1128\/JVI.02210-06","article-title":"Rab 5 Is Required for the Cellular Entry of Dengue and West Nile Viruses","volume":"81","author":"Krishnan","year":"2007","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5201","DOI":"10.1128\/JVI.73.6.5201-5206.1999","article-title":"Infection of primary cultures of human Kupffer cells by Dengue virus: No viral progeny synthesis, but cytokine production is evident","volume":"73","author":"Marianneau","year":"1999","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3390\/v3020160","article-title":"Flavivirus Cell Entry and Membrane Fusion","volume":"3","author":"Smit","year":"2011","journal-title":"Viruses"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3390\/v6010069","article-title":"Flavivirus Entry Receptors: An Update","volume":"6","author":"Meertens","year":"2013","journal-title":"Viruses"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.1073\/pnas.1720032115","article-title":"Flavivirus internalization is regulated by a size-dependent endocytic pathway","volume":"115","author":"Hackett","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wang, C., Puerta-Guardo, H., Biering, S.B., Glasner, D.R., Tran, E.B., Patana, M., Gomberg, T.A., Malvar, C., Lo, N.T.N., and Espinosa, D.A. (2019). Endocytosis of flavivirus NS1 is required for NS1-mediated endothelial hyperpermeability and is abolished by a single N-glycosylation site mutation. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007938"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Carro, S.D., and Cherry, S. (2020). Beyond the Surface: Endocytosis of Mosquito-Borne Flaviviruses. Viruses, 13.","DOI":"10.3390\/v13010013"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1111\/j.1600-0854.2005.00339.x","article-title":"Wrapping Things up about Virus RNA Replication","volume":"6","author":"MacKenzie","year":"2005","journal-title":"Traffic"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10787","DOI":"10.1128\/JVI.75.22.10787-10799.2001","article-title":"Assembly and maturation of the flavivirus Kunjin virus appear to occur in the rough endoplasmic reticulum and along the secretory pathway, respectively","volume":"75","author":"Mackenzie","year":"2001","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"24388","DOI":"10.1074\/jbc.M301717200","article-title":"Architecture of the flaviviral replication complex. Protease, nuclease, and detergents reveal encasement within double-layered membrane compartments","volume":"278","author":"Uchil","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e00055-16","DOI":"10.1128\/MMBR.00055-16","article-title":"The Antigenic Structure of Zika Virus and Its Relation to Other Flaviviruses: Implications for Infection and Immunoprophylaxis","volume":"81","author":"Heinz","year":"2017","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Wang, P.-G., Kudelko, M., Lo, J., Siu, L.Y.L., Kwok, K.T.H., Sachse, M., Nicholls, J.M., Bruzzone, R., Altmeyer, R.M., and Nal, B. (2009). Efficient Assembly and Secretion of Recombinant Subviral Particles of the Four Dengue Serotypes Using Native prM and E Proteins. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0008325"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3459","DOI":"10.1002\/1873-3468.12443","article-title":"Substrate profiling of Zika virus NS2B-NS3 protease","volume":"590","author":"Gruba","year":"2016","journal-title":"FEBS Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1128\/JVI.01788-07","article-title":"Crystal Structure of the NS3 Protease-Helicase from Dengue Virus","volume":"82","author":"Luo","year":"2008","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"18817","DOI":"10.1074\/jbc.M109.090936","article-title":"Flexibility between the Protease and Helicase Domains of the Dengue Virus NS3 Protein Conferred by the Linker Region and Its Functional Implications","volume":"285","author":"Luo","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1016\/j.febslet.2006.01.006","article-title":"Energetics of RNA binding by the West Nile virus RNA triphosphatase","volume":"580","author":"Benzaghou","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1038\/emboj.2008.232","article-title":"Insights into RNA unwinding and ATP hydrolysis by the flavivirus NS3 protein","volume":"27","author":"Luo","year":"2008","journal-title":"EMBO J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nsmb1073","article-title":"Structural basis for the activation of flaviviral NS3 proteases from dengue and West Nile virus","volume":"13","author":"Erbel","year":"2006","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/0042-6822(89)90639-9","article-title":"Detection of a trypsin-like serine protease domain in flaviviruses and pestiviruses","volume":"171","author":"Bazan","year":"1989","journal-title":"Virology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.jmgm.2015.05.008","article-title":"Binding specificity of polypeptide substrates in NS2B\/NS3pro serine protease of dengue virus type 2: A molecular dynamics Study","volume":"60","author":"Yotmanee","year":"2015","journal-title":"J. Mol. Gr. Model."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6797","DOI":"10.1128\/jvi.67.11.6797-6807.1993","article-title":"Mutagenesis of the yellow fever virus NS2B protein: Effects on proteolytic processing, NS2B-NS3 complex formation, and viral replication","volume":"67","author":"Chambers","year":"1993","journal-title":"J. Virol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.pep.2011.08.008","article-title":"Expression, purification, and initial structural characterization of nonstructural protein 2B, an integral membrane protein of Dengue-2 virus, in detergent micelles","volume":"80","author":"Huang","year":"2011","journal-title":"Protein Expr. Purif."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1006\/viro.1993.1198","article-title":"Dengue 2 Virus NS2B and NS3 Form a Stable Complex That Can Cleave NS3 within the Helicase Domain","volume":"193","author":"Arias","year":"1993","journal-title":"Virology"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1128\/jvi.69.3.1600-1605.1995","article-title":"Mutagenesis of the yellow fever virus NS2B\/3 cleavage site: Determinants of cleavage site specificity and effects on polyprotein processing and viral replication","volume":"69","author":"Chambers","year":"1995","journal-title":"J. Virol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1099\/vir.0.80427-0","article-title":"Yellow fever virus NS2B\u2013NS3 protease: Characterization of charged-to-alanine mutant and revertant viruses and analysis of polyprotein-cleavage activities","volume":"86","author":"Chambers","year":"2005","journal-title":"J. Gen. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"30715","DOI":"10.1074\/jbc.272.49.30715","article-title":"Cotranslational Membrane Insertion of the Serine Proteinase Precursor NS2B-NS3(Pro) of Dengue Virus Type 2 Is Required for Efficient in Vitro Processing and Is Mediated through the Hydrophobic Regions of NS2B","volume":"272","author":"Clum","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.antiviral.2008.08.004","article-title":"Molecular targets for flavivirus drug discovery","volume":"81","author":"Sampath","year":"2009","journal-title":"Antivir. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1128\/JVI.01325-08","article-title":"Mechanism of NS2B-Mediated Activation of NS3pro in Dengue Virus: Molecular Dynamics Simulations and Bioassays","volume":"83","author":"Zuo","year":"2009","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2034","DOI":"10.1128\/jvi.67.4.2034-2042.1993","article-title":"Deletion analysis of dengue virus type 4 nonstructural protein NS2B: Identification of a domain required for NS2B-NS3 protease activity","volume":"67","author":"Falgout","year":"1993","journal-title":"J. Virol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"12883","DOI":"10.1074\/jbc.M611318200","article-title":"Functional Characterization of cis and trans Activity of the Flavivirus NS2B-NS3 Protease","volume":"282","author":"Bera","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1110\/ps.072753207","article-title":"Structural evidence for regulation and specificity of flaviviral proteases and evolution of the Flaviviridae fold","volume":"16","author":"Aleshin","year":"2007","journal-title":"Protein Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6042","DOI":"10.1128\/jvi.65.11.6042-6050.1991","article-title":"Processing of the yellow fever virus nonstructural polyprotein: A catalytically active NS3 proteinase domain and NS2B are required for cleavages at dibasic sites","volume":"65","author":"Chambers","year":"1991","journal-title":"J. Virol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.1128\/jvi.67.4.2327-2335.1993","article-title":"Cleavage at a novel site in the NS4A region by the yellow fever virus NS2B-3 proteinase is a prerequisite for processing at the downstream 4A\/4B signalase site","volume":"67","author":"Lin","year":"1993","journal-title":"J. Virol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6218","DOI":"10.1073\/pnas.90.13.6218","article-title":"Flavivirus premembrane protein cleavage and spike heterodimer secretion require the function of the viral proteinase NS3","volume":"90","author":"Lobigs","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1007\/s12250-014-3438-6","article-title":"Functional interplay among the flavivirus NS3 protease, helicase, and cofactors","volume":"29","author":"Li","year":"2014","journal-title":"Virol. Sin."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6650","DOI":"10.1128\/jvi.71.9.6650-6661.1997","article-title":"Ultrastructure of Kunjin virus-infected cells: Colocalization of NS1 and NS3 with double-stranded RNA, and of NS2B with NS3, in virus-induced membrane structures","volume":"71","author":"Westaway","year":"1997","journal-title":"J. Virol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/jmr.977","article-title":"Homology modeling and molecular dynamics simulations of Dengue virus NS2B\/NS3 protease: Insight into molecular interaction","volume":"23","author":"Wichapong","year":"2009","journal-title":"J. Mol. Recognit."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Junaid, M., Chalayut, C., Torrejon, A.S., Angsuthanasombat, C., Shutava, I., Lapins, M., Wikberg, J.E.S., and Katzenmeier, G. (2012). Enzymatic Analysis of Recombinant Japanese Encephalitis Virus NS2B(H)-NS3pro Protease with Fluorogenic Model Peptide Substrates. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036872"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"45762","DOI":"10.1074\/jbc.M107360200","article-title":"Activity of recombinant dengue 2 virus NS3 protease in the presence of a truncated NS2B co-factor, small peptide substrates, and inhibitors","volume":"276","author":"Leung","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9963","DOI":"10.1074\/jbc.275.14.9963","article-title":"Purified NS2B\/NS3 Serine Protease of Dengue Virus Type 2 Exhibits Cofactor NS2B Dependence for Cleavage of Substrates with Dibasic Amino Acids in Vitro","volume":"275","author":"Yusof","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1128\/JVI.06225-11","article-title":"Ligand-bound structures of the dengue virus protease reveal the active conformation","volume":"86","author":"Noble","year":"2012","journal-title":"J. Virol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1128\/jvi.65.5.2467-2475.1991","article-title":"Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins","volume":"65","author":"Falgout","year":"1991","journal-title":"J. Virol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1016\/j.bbamem.2015.06.010","article-title":"Membrane topology of NS2B of dengue virus revealed by NMR spectroscopy","volume":"1848 Pt A","author":"Li","year":"2015","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2840","DOI":"10.1021\/bi2018267","article-title":"Structural Platform for the Autolytic Activity of an Intact NS2B\u2013NS3 Protease Complex from Dengue Virus","volume":"51","author":"Choksupmanee","year":"2012","journal-title":"Biochemistry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"11348","DOI":"10.1021\/cr500233q","article-title":"Biochemistry and Medicinal Chemistry of the Dengue Virus Protease","volume":"114","author":"Nitsche","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Cordero, J.G., Ju\u00e1rez, M.L., Gonz\u00e1lez-Y-Merchand, J.A., Barr\u00f3n, L.C., and Casta\u00f1eda, B.G. (2014). Caveolin-1 in Lipid Rafts Interacts with Dengue Virus NS3 during Polyprotein Processing and Replication in HMEC-1 Cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090704"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e01836-16","DOI":"10.1128\/JVI.01836-16","article-title":"Mutagenesis of Dengue Virus Protein NS2A Revealed a Novel Domain Responsible for Virus-Induced Cytopathic Effect and Interactions between NS2A and NS2B Transmembrane Segments","volume":"91","author":"Wu","year":"2017","journal-title":"J. Virol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12985-015-0456-4","article-title":"Recombinant Dengue virus protein NS2B alters membrane permeability in different membrane models","volume":"13","author":"Shrivastava","year":"2016","journal-title":"Virol. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"13708","DOI":"10.1128\/JVI.78.24.13708-13716.2004","article-title":"Identification of residues in the dengue virus type 2 NS2B cofactor that are critical for NS3 protease activation","volume":"78","author":"Niyomrattanakit","year":"2004","journal-title":"J. Virol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"17037","DOI":"10.1038\/nmicrobiol.2017.37","article-title":"Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection","volume":"2","author":"Aguirre","year":"2017","journal-title":"Nat. Microbiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"7232","DOI":"10.1128\/jvi.69.11.7232-7243.1995","article-title":"Evidence that flavivirus NS1-NS2A cleavage is mediated by a membrane-bound host protease in the endoplasmic reticulum","volume":"69","author":"Falgout","year":"1995","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1128\/jvi.68.6.3794-3802.1994","article-title":"NS2B-3 proteinase-mediated processing in the yellow fever virus structural region: In vitro and in vivo studies","volume":"68","author":"Amberg","year":"1994","journal-title":"J. Virol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1128\/jvi.66.3.1535-1542.1992","article-title":"Cleavage of the dengue virus polyprotein at the NS3\/NS4A and NS4B\/NS5 junctions is mediated by viral protease NS2B-NS3, whereas NS4A\/NS4B may be processed by a cellular protease","volume":"66","author":"Cahour","year":"1992","journal-title":"J. Virol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1128\/jvi.69.4.1995-2003.1995","article-title":"Formation of the flavivirus envelope: Role of the viral NS2B-NS3 protease","volume":"69","author":"Yamshchikov","year":"1995","journal-title":"J. Virol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1006\/viro.1994.1103","article-title":"Mutagenesis of the yellow fever virus NS2A\/2B cleavage site: Effects on proteolytic processing, viral replication, and evidence for alternative processing of the NS2A protein","volume":"199","author":"Nestorowicz","year":"1994","journal-title":"Virology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1006\/viro.2000.0488","article-title":"Yellow Fever Virus NS2B\u2013NS3 Protease: Charged-to-Alanine Mutagenesis and Deletion Analysis Define Regions Important for Protease Complex Formation and Function","volume":"275","author":"Droll","year":"2000","journal-title":"Virology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1038\/cr.2016.116","article-title":"Mechanisms of activation and inhibition of Zika virus NS2B-NS3 protease","volume":"26","author":"Chen","year":"2016","journal-title":"Cell Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1126\/science.aag2419","article-title":"Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor","volume":"353","author":"Lei","year":"2016","journal-title":"Science"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.antiviral.2016.12.016","article-title":"Identification of novel small molecule inhibitors against NS2B\/NS3 serine protease from Zika virus","volume":"139","author":"Lee","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3389\/fcimb.2016.00144","article-title":"Intrinsically Disordered Side of the Zika Virus Proteome","volume":"6","author":"Giri","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1039\/C6MB00228E","article-title":"Correlating Flavivirus virulence and levels of intrinsic disorder in shell proteins: Protective roles vs. immune evasion","volume":"12","author":"Goh","year":"2016","journal-title":"Mol. BioSyst."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Hameed, M., Wahaab, A., Nawaz, M., Khan, S., Nazir, J., Liu, K., Wei, J., and Ma, Z. (2021). Potential Role of Birds in Japanese Encephalitis Virus Zoonotic Transmission and Genotype Shift. Viruses, 13.","DOI":"10.20944\/preprints202101.0549.v1"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1089\/vbz.2018.2291","article-title":"Changing Geographic Distribution of Japanese Encephalitis Virus Genotypes, 1935\u20132017","volume":"19","author":"Gao","year":"2019","journal-title":"Vector Borne Zoonotic Dis."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Anwar, N., Wang, X., Hameed, M., Wahaab, A., Li, C., Sharma, M., Pang, L., Malik, M.I., Liu, K., and Li, B. (2020). Phenotypic and Genotypic Comparison of a Live-Attenuated Genotype I Japanese Encephalitis Virus SD12-F120 Strain with Its Virulent Parental SD12 Strain. Viruses, 12.","DOI":"10.3390\/v12050552"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Anwar, M.N., Jiang, C., Di, D., Zhang, J., Guo, S., Wang, X., Hameed, M., Wahaab, A., Shao, D., and Li, Z. (2021). A Novel Recombinant Virus-Like Particles Displaying B and T Cell Epitopes of Japanese Encephalitis Virus Offers Protective Immunity in Mice and Guinea Pigs. Vaccines, 9.","DOI":"10.3390\/vaccines9090980"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1099\/0022-1317-79-5-947","article-title":"Virus-encoded proteinases of the Flaviviridae","volume":"79","author":"Ryan","year":"1998","journal-title":"J. Gen. Virol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5735","DOI":"10.1128\/JVI.00340-16","article-title":"Transmembrane Domains of NS2B Contribute to both Viral RNA Replication and Particle Formation in Japanese Encephalitis Virus","volume":"90","author":"Li","year":"2016","journal-title":"J. Virol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.antiviral.2015.03.014","article-title":"The flavivirus NS2B\u2013NS3 protease\u2013helicase as a target for antiviral drug development","volume":"118","author":"Luo","year":"2015","journal-title":"Antivir. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2746","DOI":"10.1016\/j.vaccine.2009.03.007","article-title":"A Japanese encephalitis virus vaccine candidate strain is attenuated by decreasing its interferon antagonistic ability","volume":"27","author":"Liang","year":"2009","journal-title":"Vaccine"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Fan, Y.-C., Liang, J.-J., Chen, J.-M., Lin, J.-W., Chen, Y.-Y., Su, K.-H., Lin, C.-C., Tu, W.-C., Chiou, M.-T., and Ou, S.-C. (2019). NS2B\/NS3 mutations enhance the infectivity of genotype I Japanese encephalitis virus in amplifying hosts. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007992"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.virusres.2007.03.022","article-title":"Functional determinants of NS2B for activation of Japanese encephalitis virus NS3 protease","volume":"127","author":"Lin","year":"2007","journal-title":"Virus Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1099\/vir.0.83447-0","article-title":"Mutagenesis of the West Nile virus NS2B cofactor domain reveals two regions essential for protease activity","volume":"89","author":"Chappell","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/prot.21129","article-title":"Homology modeling and molecular dynamics study of West Nile virus NS3 protease: A molecular basis for the catalytic activity increased by the NS2B cofactor","volume":"65","author":"Zhou","year":"2006","journal-title":"Proteins"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.2174\/092986708786242804","article-title":"West Nile Virus NS2B\/NS3 Protease As An Antiviral Target","volume":"15","author":"Chappell","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1007\/s12250-013-3276-y","article-title":"Mutagenesis of D80-82 and G83 residues in West Nile Virus NS2B: Effects on NS2B-NS3 activity and viral replication","volume":"28","author":"Jia","year":"2013","journal-title":"Virol. Sin."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"17270","DOI":"10.1074\/jbc.M801719200","article-title":"The Two-component NS2B-NS3 Proteinase Represses DNA Unwinding Activity of the West Nile Virus NS3 Helicase","volume":"283","author":"Chernov","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4640","DOI":"10.3390\/v7082837","article-title":"Flaviviral Replication Complex: Coordination between RNA Synthesis and 5\u2032-RNA Capping","volume":"7","author":"Klema","year":"2015","journal-title":"Viruses"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.febslet.2009.01.008","article-title":"Analysis of the nucleoside triphosphatase, RNA triphosphatase, and unwinding activities of the helicase domain of dengue virus NS3 protein","volume":"583","author":"Wang","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_116","doi-asserted-by":"crossref","unstructured":"Su, X.-C., Ozawa, K., Qi, R., Vasudevan, S., Lim, S.P., and Otting, G. (2009). NMR Analysis of the Dynamic Exchange of the NS2B Cofactor between Open and Closed Conformations of the West Nile Virus NS2B-NS3 Protease. PLoS Negl. Trop. Dis., 3.","DOI":"10.1371\/journal.pntd.0000561"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1016\/j.jmb.2008.11.026","article-title":"Structure of West Nile Virus NS3 Protease: Ligand Stabilization of the Catalytic Conformation","volume":"385","author":"Robin","year":"2009","journal-title":"J. Mol. Biol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"48535","DOI":"10.1074\/jbc.M406810200","article-title":"Enzymatic Characterization and Homology Model of a Catalytically Active Recombinant West Nile Virus NS3 Protease","volume":"279","author":"Nall","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jviromet.2003.09.001","article-title":"Activation of dengue protease autocleavage at the NS2B\u2013NS3 junction by recombinant NS3 and GST\u2013NS2B fusion proteins","volume":"114","author":"Wu","year":"2003","journal-title":"J. Virol. Methods"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"3279","DOI":"10.1099\/vir.0.82088-0","article-title":"Mutagenesis analysis of the NS2B determinants of the Alkhurma virus NS2B\u2013NS3 protease activation","volume":"87","author":"Pastorino","year":"2006","journal-title":"J. Gen. Virol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.virusres.2009.03.007","article-title":"Japanese encephalitis virus NS2B-NS3 protease induces caspase 3 activation and mitochondria-mediated apoptosis in human medulloblastoma cells","volume":"143","author":"Yang","year":"2009","journal-title":"Virus Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"38448","DOI":"10.1074\/jbc.M607641200","article-title":"Insights to substrate binding and processing by West Nile Virus NS3 protease through combined modeling, protease mutagenesis, and kinetic studies","volume":"281","author":"Chappell","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"8632","DOI":"10.1128\/JVI.01253-15","article-title":"Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly","volume":"89","author":"VanBlargan","year":"2015","journal-title":"J. Virol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4749","DOI":"10.1128\/jvi.65.9.4749-4758.1991","article-title":"Flavivirus enzyme-substrate interactions studied with chimeric proteinases: Identification of an intragenic locus important for substrate recognition","volume":"65","author":"Preugschat","year":"1991","journal-title":"J. Virol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"10136","DOI":"10.1073\/pnas.1805195115","article-title":"Targeting intramolecular proteinase NS2B\/3 cleavages for trans-dominant inhibition of dengue virus","volume":"115","author":"Constant","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1099\/0022-1317-78-2-337","article-title":"Internal proteolysis of the NS3 protein specified by dengue virus 2","volume":"78","author":"Teo","year":"1997","journal-title":"J. Gen. Virol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.antiviral.2017.04.015","article-title":"Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists","volume":"143","author":"Shiryaev","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"17345","DOI":"10.1073\/pnas.1010811107","article-title":"Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis","volume":"107","author":"Heaton","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"6793","DOI":"10.1128\/JVI.00045-14","article-title":"Rab18 Facilitates Dengue Virus Infection by Targeting Fatty Acid Synthase to Sites of Viral Replication","volume":"88","author":"Tang","year":"2014","journal-title":"J. Virol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1038\/s41598-019-39157-7","article-title":"Dengue virus nonstructural 3 protein interacts directly with human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and reduces its glycolytic activity","volume":"9","author":"Silva","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.1158\/0008-5472.CAN-04-3954","article-title":"Glyceraldehyde-3-Phosphate Dehydrogenase Binds to the AU-Rich 3\u2032 Untranslated Region of Colony-Stimulating Factor\u20131 (CSF-1) Messenger RNA in Human Ovarian Cancer Cells: Possible Role in CSF-1 Posttranscriptional Regulation and Tumor Phenotype","volume":"65","author":"Folk","year":"2005","journal-title":"Cancer Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.abb.2012.09.004","article-title":"Glyceraldehyde-3-phosphate dehydrogenase regulates cyclooxygenase-2 expression by targeting mRNA stability","volume":"528","author":"Ikeda","year":"2012","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Riedl, W., Acharya, D., Lee, J.-H., Liu, G., Serman, T., Chiang, C., Chan, Y.K., Diamond, M.S., and Gack, M.U. (2019). Zika Virus NS3 Mimics a Cellular 14-3-3-Binding Motif to Antagonize RIG-I- and MDA5-Mediated Innate Immunity. Cell Host Microbe, 26.","DOI":"10.1016\/j.chom.2019.09.012"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"6331","DOI":"10.1038\/sj.onc.1204777","article-title":"14-3-3 proteins; bringing new definitions to scaffolding","volume":"20","author":"Tzivion","year":"2001","journal-title":"Oncogene"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1080\/15548627.2016.1265192","article-title":"Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B","volume":"13","author":"Lennemann","year":"2017","journal-title":"Autophagy"},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Li, H., Saucedo-Cuevas, L., Yuan, L., Ross, D., Johansen, A., Sands, D., Stanley, V., Guemez-Gamboa, A., Gregor, A., and Evans, T. (2019). Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors. Neuron, 101.","DOI":"10.1016\/j.neuron.2019.01.010"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.bbrc.2016.03.120","article-title":"DDX21 translocates from nucleus to cytoplasm and stimulates the innate immune response due to dengue virus infection","volume":"473","author":"Dong","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Cao, Y.-Q., Yuan, L., Zhao, Q., Yuan, J.-L., Miao, C., Chang, Y.-F., Wen, X.-T., Wu, R., Huang, X.-B., and Wen, Y.-P. (2019). Hsp40 Protein DNAJB6 Interacts with Viral NS3 and Inhibits the Replication of the Japanese Encephalitis Virus. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20225719"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nrmicro.2017.170","article-title":"Rewiring cellular networks by members of the Flaviviridae family","volume":"16","author":"Neufeldt","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Yu, C.Y., Liang, J.J., Li, J.K., Lee, Y.L., Chang, B.L., Su, C.I., Huang, W.J., Lai, M.M., and Lin, Y.L. (2015). Dengue Virus Impairs Mitochondrial Fusion by Cleaving Mitofusins. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005350"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"e01178-20","DOI":"10.1128\/JVI.01178-20","article-title":"Mitochondrial Import of Dengue Virus NS3 Protease and Cleavage of GrpEL1, a Cochaperone of Mitochondrial Hsp70","volume":"94","author":"Gandikota","year":"2020","journal-title":"J. Virol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/j.jmb.2015.10.001","article-title":"Breaching the Barrier\u2014The Nuclear Envelope in Virus Infection","volume":"428","author":"Mettenleiter","year":"2016","journal-title":"J. Mol. Biol."},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"De Jes\u00fas-Gonz\u00e1lez, L.A., Palacios-R\u00e1palo, S., Reyes-Ruiz, J.M., Osuna-Ramos, J.F., Cordero-Rivera, C.D., Farfan-Morales, C.N., Guti\u00e9rrez-Escolano, A.L., and Del \u00c1ngel, R.M. (2021). The Nuclear Pore Complex Is a Key Target of Viral Proteases to Promote Viral Replication. Viruses, 13.","DOI":"10.3390\/v13040706"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"De Jes\u00fas-Gonz\u00e1lez, L.A., Cervantes-Salazar, M., Reyes-Ruiz, J.M., Osuna-Ramos, J.F., Farf\u00e1n-Morales, C.N., Palacios-R\u00e1palo, S.N., P\u00e9rez-Olais, J.H., Cordero-Rivera, C.D., Hurtado-Monz\u00f3n, A.M., and Ru\u00edz-Jim\u00e9nez, F. (2020). The Nuclear Pore Complex: A Target for NS3 Protease of Dengue and Zika Viruses. Viruses, 12.","DOI":"10.3390\/v12060583"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.gene.2017.07.049","article-title":"Molecular cloning and characterization of the genes encoding the proteins of Zika virus","volume":"628","author":"Hou","year":"2017","journal-title":"Gene"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1016\/j.celrep.2017.02.014","article-title":"Ultrastructural Characterization of Zika Virus Replication Factories","volume":"18","author":"Cortese","year":"2017","journal-title":"Cell Rep."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.virol.2017.12.014","article-title":"Strand-like structures and the nonstructural proteins 5, 3 and 1 are present in the nucleus of mosquito cells infected with dengue virus","volume":"515","author":"Guillen","year":"2018","journal-title":"Virology"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1007\/s00705-021-05026-w","article-title":"Nuclear localization of non-structural protein 3 (NS3) during dengue virus infection","volume":"166","year":"2021","journal-title":"Arch. Virol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1128\/JVI.02719-06","article-title":"Switching the Substrate Specificity of the Two-Component NS2B-NS3 Flavivirus Proteinase by Structure-Based Mutagenesis","volume":"81","author":"Shiryaev","year":"2007","journal-title":"J. Virol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1099\/0022-1317-76-3-573","article-title":"Processing of Japanese encephalitis virus non-structural proteins: NS2B-NS3 complex and heterologous proteases","volume":"76","author":"Jan","year":"1995","journal-title":"J. Gen. Virol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/0042-6822(87)90144-9","article-title":"Complete nucleotide sequence of the Japanese encephalitis virus genome RNA","volume":"161","author":"Sumiyoshi","year":"1987","journal-title":"Virology"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1126\/science.4023707","article-title":"Nucleotide sequence of yellow fever virus: Implications for flavivirus gene expression and evolution","volume":"229","author":"Rice","year":"1985","journal-title":"Science"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/0042-6822(85)90129-1","article-title":"Sequence analysis of the membrane protein V3 of the flavivirus west nile virus and of its gene","volume":"147","author":"Wengler","year":"1985","journal-title":"Virology"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/0042-6822(86)90082-6","article-title":"Primary structure of the West Nile flavivirus genome region coding for all nonstructural proteins","volume":"149","author":"Castle","year":"1986","journal-title":"Virology"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1128\/jvi.63.6.2521-2526.1989","article-title":"Cell-associated West Nile flavivirus is covered with E+pre-M protein heterodimers which are destroyed and reorganized by proteolytic cleavage during virus release","volume":"63","author":"Wengler","year":"1989","journal-title":"J. Virol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1006\/viro.1995.1226","article-title":"Complete Nucleotide Sequences of 5\u2032- and 3\u2032-Noncoding Regions of Both Genome Segments of Different Strains of Infectious Bursal Disease Virus","volume":"209","author":"Mundt","year":"1995","journal-title":"Virology"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.antiviral.2019.02.001","article-title":"Proteolytic cleavage of host proteins by the Group IV viral proteases of Venezuelan equine encephalitis virus and Zika virus","volume":"164","author":"Morazzani","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/0042-6822(87)90196-6","article-title":"Sequence of the dengue-1 virus genome in the region encoding the three structural proteins and the major nonstructural protein NS1","volume":"161","author":"Mason","year":"1987","journal-title":"Virology"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/0042-6822(88)90406-0","article-title":"Nucleotide sequence of dengue 2 RNA and comparison of the encoded proteins with those of other flaviviruses","volume":"162","author":"Hahn","year":"1988","journal-title":"Virology"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/BF00569739","article-title":"Nucleotide sequence of dengue type 3 virus genomic RNA encoding viral structural proteins","volume":"2","author":"Osatomi","year":"1988","journal-title":"Virus Genes"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/0042-6822(87)90458-2","article-title":"The nucleotide sequence of dengue type 4 virus: Analysis of genes coding for nonstructural proteins","volume":"159","author":"Mackow","year":"1987","journal-title":"Virology"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0042-6822(86)90169-8","article-title":"Cloning full-length dengue type 4 viral DNA sequences: Analysis of genes coding for structural proteins","volume":"155","author":"Zhao","year":"1986","journal-title":"Virology"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.biocel.2006.10.025","article-title":"Characterization of the West Nile virus protease substrate specificity and inhibitors","volume":"39","author":"Mueller","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Li, Y., Zhang, Z., Phoo, W.W., Loh, Y.R., Wang, W., Liu, S., Chen, M.W., Hung, A.W., Keller, T.H., and Luo, D. (2017). Structural Dynamics of Zika Virus NS2B-NS3 Protease Binding to Dipeptide Inhibitors. Structure, 25.","DOI":"10.1016\/j.str.2017.06.006"},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"13410","DOI":"10.1038\/ncomms13410","article-title":"Structure of the NS2B-NS3 protease from Zika virus after self-cleavage","volume":"7","author":"Phoo","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.bbrc.2011.03.054","article-title":"Yellow fever virus NS2B\/NS3 protease: Hydrolytic Properties and Substrate Specificity","volume":"407","author":"Kondo","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1128\/CMR.00102-15","article-title":"Approved Antiviral Drugs over the Past 50 Years","volume":"29","author":"Li","year":"2016","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.antiviral.2013.09.013","article-title":"Ten years of dengue drug discovery: Progress and prospects","volume":"100","author":"Lim","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1042\/BJ20051767","article-title":"Probing the substrate specificity of the dengue virus type 2 NS3 serine protease by using internally quenched fluorescent peptides","volume":"397","author":"Niyomrattanakit","year":"2006","journal-title":"Biochem. J."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.bmcl.2005.09.049","article-title":"Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors","volume":"16","author":"Yin","year":"2006","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"4848","DOI":"10.1016\/j.bmcl.2013.06.081","article-title":"A FRET-based assay for the discovery of West Nile Virus NS2B-NS3 protease inhibitors","volume":"23","author":"Adamek","year":"2013","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"9354","DOI":"10.1021\/acs.jmedchem.5b01441","article-title":"Discovery of Nanomolar Dengue and West Nile Virus Protease Inhibitors Containing a 4-Benzyloxyphenylglycine Residue","volume":"58","author":"Behnam","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1021\/acs.jmedchem.6b01021","article-title":"Peptide\u2013Boronic Acid Inhibitors of Flaviviral Proteases: Medicinal Chemistry and Structural Biology","volume":"60","author":"Nitsche","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.antiviral.2011.07.002","article-title":"Tripeptide inhibitors of dengue and West Nile virus NS2B-NS3 protease","volume":"92","author":"Yin","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1042\/BJ20051374","article-title":"Cleavage targets and the D-arginine-based inhibitors of the West Nile virus NS3 processing proteinase","volume":"393","author":"Shiryaev","year":"2006","journal-title":"Biochem. J."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"5714","DOI":"10.1021\/jm800503y","article-title":"Potent cationic inhibitors of West Nile virus NS2B\/NS3 protease with serum stability, cell permeability and antiviral activity","volume":"51","author":"Stoermer","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"6585","DOI":"10.1021\/jm0607606","article-title":"Peptide Inhibitors of West Nile NS3 Protease: SAR Study of Tetrapeptide Aldehyde Inhibitors","volume":"49","author":"Knox","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1021\/ml500245v","article-title":"C-Terminal Residue Optimization and Fragment Merging: Discovery of a Potent Peptide-Hybrid Inhibitor of Dengue Protease","volume":"5","author":"Behnam","year":"2014","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1016\/j.bmc.2015.07.012","article-title":"Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids","volume":"23","author":"Behnam","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1007\/s00705-010-0702-4","article-title":"Identification of palmatine as an inhibitor of West Nile virus","volume":"155","author":"Jia","year":"2010","journal-title":"Arch. Virol."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3851\/IMP1767","article-title":"Small Molecule Pan-Dengue and West Nile Virus NS3 Protease Inhibitors","volume":"21","author":"Jiao","year":"2011","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1080\/14756366.2017.1306521","article-title":"Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication","volume":"32","author":"Kouretova","year":"2017","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"8389","DOI":"10.1021\/jm400828u","article-title":"Thiazolidinone\u2013Peptide Hybrids as Dengue Virus Protease Inhibitors with Antiviral Activity in Cell Culture","volume":"56","author":"Nitsche","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1089\/omi.2013.0056","article-title":"Antiviral Cationic Peptides as a Strategy for Innovation in Global Health Therapeutics for Dengue Virus: High Yield Production of the Biologically Active Recombinant Plectasin Peptide","volume":"17","author":"Rothan","year":"2013","journal-title":"OMICS J. Integr. Biol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"7719","DOI":"10.1021\/acs.jmedchem.5b00612","article-title":"Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors","volume":"58","author":"Weigel","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"250","DOI":"10.6026\/97320630005250","article-title":"Designing cyclic peptide inhibitor of dengue virus NS3-NS2B protease by using molecular docking approach","volume":"5","author":"Tambunan","year":"2010","journal-title":"Bioinformation"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1128\/AAC.00855-10","article-title":"Novel dengue virus-specific NS2B\/NS3 protease inhibitor, BP2109, discovered by a high-throughput screening assay","volume":"55","author":"Yang","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1128\/AAC.01281-13","article-title":"A Novel Dengue Virus Inhibitor, BP13944, Discovered by High-Throughput Screening with Dengue Virus Replicon Cells Selects for Resistance in the Viral NS2B\/NS3 Protease","volume":"58","author":"Yang","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"385","DOI":"10.3851\/IMP3231","article-title":"A quinoline compound inhibits the replication of dengue virus serotypes 1\u20134 in Vero cells","volume":"23","author":"Beesetti","year":"2018","journal-title":"Antivir. Ther."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"4140","DOI":"10.1016\/j.bmc.2012.04.055","article-title":"Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold","volume":"20","author":"Aravapalli","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1021\/acs.jmedchem.0c02070","article-title":"Synthesis, Structure-Activity Relationships, and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease","volume":"64","author":"Nie","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"251482","DOI":"10.1155\/2012\/251482","article-title":"Protegrin-1 Inhibits Dengue NS2B-NS3 Serine Protease and Viral Replication in MK2 Cells","volume":"2012","author":"Rothan","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"ref_193","doi-asserted-by":"crossref","unstructured":"Rothan, H.A., Han, H.C., Ramasamy, T.S., Othman, S., Rahman, N.A., and Yusof, R. (2012). Inhibition of dengue NS2B-NS3 protease and viral replication in Vero cells by recombinant retrocyclin-1. BMC Infect. Dis., 12.","DOI":"10.1186\/1471-2334-12-314"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1016\/j.bmcl.2005.12.075","article-title":"Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda (L.), towards dengue-2 virus NS3 protease","volume":"16","author":"Kiat","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.antiviral.2011.12.003","article-title":"Use of parallel validation high-throughput screens to reduce false positives and identify novel dengue NS2B-NS3 protease inhibitors","volume":"93","author":"Tomlinson","year":"2012","journal-title":"Antivir. Res."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.antiviral.2012.02.008","article-title":"Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease","volume":"94","author":"Nitsche","year":"2012","journal-title":"Antivir. Res."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.antiviral.2017.02.002","article-title":"Novel antiviral activity and mechanism of bromocriptine as a Zika virus NS2B-NS3 protease inhibitor","volume":"141","author":"Chan","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.antiviral.2017.07.007","article-title":"Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo","volume":"145","author":"Yuan","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"18132","DOI":"10.1021\/acsomega.8b01002","article-title":"Hydroxychloroquine Inhibits Zika Virus NS2B-NS3 Protease","volume":"3","author":"Kumar","year":"2018","journal-title":"ACS Omega"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.antiviral.2017.12.018","article-title":"Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease","volume":"150","author":"Li","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"514313","DOI":"10.3389\/fphar.2020.514313","article-title":"Identification of Theaflavin-3,3\u2019-Digallate as a Novel Zika Virus Protease Inhibitor","volume":"11","author":"Cui","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"5526","DOI":"10.1080\/07391102.2019.1704882","article-title":"Identification of a C2-symmetric diol based human immunodeficiency virus protease inhibitor targeting Zika virus NS2B-NS3 protease","volume":"38","author":"Akaberi","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_203","doi-asserted-by":"crossref","unstructured":"Brecher, M., Li, Z., Liu, B., Zhang, J., Koetzner, C.A., Alifarag, A., Jones, S.A., Lin, Q., Kramer, L.D., and Li, H. (2017). A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus NS2B-NS3 protease. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006411"},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1006\/viro.1999.9887","article-title":"Development of a novel mouse model for dengue virus infection","volume":"263","author":"An","year":"1999","journal-title":"Virology"},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"13797","DOI":"10.1128\/JVI.79.21.13797-13799.2005","article-title":"Dengue Fever in Humanized NOD\/SCID Mice","volume":"79","author":"Bente","year":"2005","journal-title":"J. Virol."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"7637","DOI":"10.1128\/JVI.00534-12","article-title":"Mosquito bite delivery of dengue virus enhances immunogenicity and pathogenesis in humanized mice","volume":"86","author":"Cox","year":"2012","journal-title":"J. Virol."},{"key":"ref_207","doi-asserted-by":"crossref","unstructured":"Jaiswal, S., Pearson, T., Friberg, H., Shultz, L.D., Greiner, D.L., Rothman, A.L., and Mathew, A. (2009). Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007251"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1365-2567.2012.03585.x","article-title":"Enhanced humoral and HLA-A2-restricted dengue virus-specific T-cell responses in humanized BLT NSG mice","volume":"136","author":"Jaiswal","year":"2012","journal-title":"Immunology"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.virol.2007.06.005","article-title":"Dengue virus infection and immune response in humanized RAG2(-\/-)gamma(c)(-\/-) (RAG-hu) mice","volume":"369","author":"Kuruvilla","year":"2007","journal-title":"Virology"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"9729","DOI":"10.1128\/JVI.72.12.9729-9737.1998","article-title":"Study of Dengue Virus Infection in SCID Mice Engrafted with Human K562 Cells","volume":"72","author":"Lin","year":"1998","journal-title":"J. Virol."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"8638","DOI":"10.1128\/JVI.00581-09","article-title":"Humanized Mice Show Clinical Signs of Dengue Fever according to Infecting Virus Genotype","volume":"83","author":"Mota","year":"2009","journal-title":"J. Virol."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"11648","DOI":"10.1128\/JVI.01156-13","article-title":"Inhibition of Megakaryocyte Development in the Bone Marrow Underlies Dengue Virus-Induced Thrombocytopenia in Humanized Mice","volume":"87","author":"Sridharan","year":"2013","journal-title":"J. Virol."},{"key":"ref_213","doi-asserted-by":"crossref","unstructured":"Hilgenfeld, R., and Vasudevan, S.G. (2018). Animal Models for Dengue and Zika Vaccine Development. Dengue and Zika: Control and Antiviral Treatment Strategies, Springer.","DOI":"10.1007\/978-981-10-8727-1"},{"key":"ref_214","doi-asserted-by":"crossref","unstructured":"Coronel-Ruiz, C., Guti\u00e9rrez-Barbosa, H., Medina-Moreno, S., Velandia-Romero, M.L., Chua, J.V., Castellanos, J.E., and Zapata, J.C. (2020). Humanized Mice in Dengue Research: A Comparison with Other Mouse Models. Vaccines, 8.","DOI":"10.3390\/vaccines8010039"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"E6310","DOI":"10.1073\/pnas.1803406115","article-title":"Species-specific disruption of STING-dependent antiviral cellular defenses by the Zika virus NS2B3 protease","volume":"115","author":"Ding","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ni.2491","article-title":"STING and the innate immune response to nucleic acids in the cytosol","volume":"14","author":"Burdette","year":"2013","journal-title":"Nat. Immunol."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/nature08476","article-title":"STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity","volume":"461","author":"Ishikawa","year":"2009","journal-title":"Nature"},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nature07317","article-title":"STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling","volume":"455","author":"Ishikawa","year":"2008","journal-title":"Nature"},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.immuni.2008.09.003","article-title":"The Adaptor Protein MITA Links Virus-Sensing Receptors to IRF3 Transcription Factor Activation","volume":"29","author":"Zhong","year":"2008","journal-title":"Immunity"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/ni.2091","article-title":"The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells","volume":"12","author":"Zhang","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"10680","DOI":"10.1038\/ncomms10680","article-title":"Influenza A virus targets a cGAS-independent STING pathway that controls enveloped RNA viruses","volume":"7","author":"Holm","year":"2016","journal-title":"Nature Commun."},{"key":"ref_222","doi-asserted-by":"crossref","unstructured":"Aguirre, S., Maestre, A.M., Pagni, S., Patel, J.R., Savage, T., Gutman, D., Maringer, K., Bernal-Rubio, D., Shabman, R.S., and Simon, V. (2012). DENV Inhibits Type I IFN Production in Infected Cells by Cleaving Human STING. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002934"},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/hep.26017","article-title":"Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type I interferon-dependent innate immunity","volume":"57","author":"Nitta","year":"2013","journal-title":"Hepatology"},{"key":"ref_224","doi-asserted-by":"crossref","unstructured":"Sun, L., Xing, Y., Chen, X., Zheng, Y., Yang, Y., Nichols, D.B., Clementz, M.A., Banach, B.S., Li, K., and Baker, S.C. (2012). Coronavirus Papain-like Proteases Negatively Regulate Antiviral Innate Immune Response through Disruption of STING-Mediated Signaling. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0030802"},{"key":"ref_225","doi-asserted-by":"crossref","unstructured":"Yu, C.-Y., Chang, T.-H., Liang, J.-J., Chiang, R.-L., Lee, Y.-L., Liao, C.-L., and Lin, Y.-L. (2012). Dengue Virus Targets the Adaptor Protein MITA to Subvert Host Innate Immunity. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002780"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"e31919","DOI":"10.7554\/eLife.31919","article-title":"Dengue viruses cleave STING in humans but not in nonhuman primates, their presumed natural reservoir","volume":"7","author":"Stabell","year":"2018","journal-title":"eLife"},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.chom.2010.10.007","article-title":"Mouse STAT2 Restricts Early Dengue Virus Replication","volume":"8","author":"Ashour","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"5414","DOI":"10.1128\/JVI.79.9.5414-5420.2005","article-title":"Dengue Virus Inhibits Alpha Interferon Signaling by Reducing STAT2 Expression","volume":"79","author":"Jones","year":"2005","journal-title":"J. Virol."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1086\/605847","article-title":"Dengue Virus NS5 Inhibits Interferon-\u03b1 Signaling by Blocking Signal Transducer and Activator of Transcription 2 Phosphorylation","volume":"200","author":"Mazzon","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3390\/v4030397","article-title":"Innate Immunity Evasion by Dengue Virus","volume":"4","author":"Morrison","year":"2012","journal-title":"Viruses"},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"62","DOI":"10.3390\/v4010062","article-title":"Animal Models of Dengue Virus Infection","volume":"4","author":"Zompi","year":"2012","journal-title":"Viruses"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1093\/infdis\/174.6.1176","article-title":"Development of a Purified, Inactivated, Dengue-2 Virus Vaccine Prototype in Vero Cells: Immunogenicity and Protection in Mice and Rhesus Monkeys","volume":"174","author":"Putnak","year":"1996","journal-title":"J. Infect. Dis."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1016\/S0264-410X(00)00121-3","article-title":"Immunization of rhesus monkeys with a recombinant of modified vaccinia virus Ankara expressing a truncated envelope glycoprotein of dengue type 2 virus induced resistance to dengue type 2 virus challenge","volume":"18","author":"Men","year":"2000","journal-title":"Vaccine"},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"469","DOI":"10.4269\/ajtmh.2003.68.469","article-title":"Vaccination of rhesus macaques against dengue-2 virus with a plasmid DNA vaccine encoding the viral pre-membrane and envelope genes","volume":"68","author":"Putnak","year":"2003","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1099\/0022-1317-81-7-1659","article-title":"Dengue virus type 1 DNA vaccine induces protective immune responses in rhesus macaques","volume":"81","author":"Raviprakash","year":"2000","journal-title":"Microbiology"},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.virol.2006.05.005","article-title":"A chimeric tetravalent dengue DNA vaccine elicits neutralizing antibody to all four virus serotypes in rhesus macaques","volume":"353","author":"Raviprakash","year":"2006","journal-title":"Virology"},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"6927","DOI":"10.1128\/JVI.02724-07","article-title":"A Tetravalent Dengue Vaccine Based on a Complex Adenovirus Vector Provides Significant Protection in Rhesus Monkeys against All Four Serotypes of Dengue Virus","volume":"82","author":"Raviprakash","year":"2008","journal-title":"J. Virol."},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"11411","DOI":"10.1128\/JVI.00876-14","article-title":"Rational Design of Human Metapneumovirus Live Attenuated Vaccine Candidates by Inhibiting Viral mRNA Cap Methyltransferase","volume":"88","author":"Zhang","year":"2014","journal-title":"J. Virol."},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"698","DOI":"10.4269\/ajtmh.14-0268","article-title":"An Adjuvanted, Tetravalent Dengue Virus Purified Inactivated Vaccine Candidate Induces Long-Lasting and Protective Antibody Responses Against Dengue Challenge in Rhesus Macaques","volume":"92","author":"Fernandez","year":"2015","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.1016\/j.vaccine.2016.03.108","article-title":"Evaluation of protection induced by a dengue virus serotype 2 envelope domain III protein scaffold\/DNA vaccine in non-human primates","volume":"34","author":"McBurney","year":"2016","journal-title":"Vaccine"},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/S0264-410X(98)00393-4","article-title":"Induction of protective immunity against Dengue virus type 2: Comparison of candidate live attenuated and recombinant vaccines","volume":"17","author":"Velzing","year":"1999","journal-title":"Vaccine"},{"key":"ref_242","first-page":"589","article-title":"Chimeric dengue type 2\/type 1 viruses induce immune responses in cynomolgus monkeys","volume":"33","author":"Butrapet","year":"2002","journal-title":"S. Asian J. Trop. Med. Public Health"},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"3165","DOI":"10.1016\/j.vaccine.2006.01.036","article-title":"A recombinant fusion protein containing the domain III of the dengue-2 envelope protein is immunogenic and protective in nonhuman primates","volume":"24","author":"Hermida","year":"2006","journal-title":"Vaccine"},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.virusres.2008.08.008","article-title":"Serotype-specificity of recombinant fusion proteins containing domain III of dengue virus","volume":"138","author":"Izquierdo","year":"2008","journal-title":"Virus Res."},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"978","DOI":"10.4269\/ajtmh.2011.10-0592","article-title":"Efficacy of a Tetravalent Chimeric Dengue Vaccine (DENVax) in Cynomolgus Macaques","volume":"84","author":"Osorio","year":"2011","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_246","doi-asserted-by":"crossref","unstructured":"Strouts, F.R., Popper, S.J., Partidos, C.D., Stinchcomb, D.T., Osorio, J.E., and Relman, D.A. (2016). Early Transcriptional Signatures of the Immune Response to a Live Attenuated Tetravalent Dengue Vaccine Candidate in Non-human Primates. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004731"},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"5613","DOI":"10.1016\/j.vaccine.2015.08.090","article-title":"Generation and preclinical immunogenicity study of dengue type 2 virus-like particles derived from stably transfected mosquito cells","volume":"33","author":"Suphatrakul","year":"2015","journal-title":"Vaccine"},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1099\/0022-1317-81-9-2177","article-title":"Manifestation of thrombocytopenia in dengue-2-virus-infected mice","volume":"81","author":"Huang","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1128\/JVI.78.6.2701-2710.2004","article-title":"Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T- and B-cell-dependent immunity are less critical","volume":"78","author":"Shresta","year":"2004","journal-title":"J. Virol."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"10208","DOI":"10.1128\/JVI.00062-06","article-title":"Murine Model for Dengue Virus-Induced Lethal Disease with IncreasedVascular Permeability","volume":"80","author":"Shresta","year":"2006","journal-title":"J. Virol."},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1086\/511310","article-title":"A Dengue Fever Viremia Model in Mice Shows Reduction in Viral Replication and Suppression of the Inflammatory Response after Treatment with Antiviral Drugs","volume":"195","author":"Schul","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1099\/vir.0.045088-0","article-title":"Characterization of a model of lethal dengue virus 2 infection in C57BL\/6 mice deficient in the alpha\/beta interferon receptor","volume":"93","author":"Orozco","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"8276","DOI":"10.1128\/JVI.00365-09","article-title":"Cardif-mediated signaling controls the initial innate response to dengue virus in vivo","volume":"83","author":"Perry","year":"2009","journal-title":"J. Virol."},{"key":"ref_254","doi-asserted-by":"crossref","unstructured":"Perry, S.T., Buck, M., Lada, S.M., Schindler, C., and Shresta, S. (2011). STAT2 Mediates Innate Immunity to Dengue Virus in the Absence of STAT1 via the Type I Interferon Receptor. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1001297"},{"key":"ref_255","doi-asserted-by":"crossref","first-page":"4761","DOI":"10.1128\/JVI.78.9.4761-4775.2004","article-title":"Safety and Efficacy of Chimeric Yellow Fever-Dengue Virus Tetravalent Vaccine Formulations in Nonhuman Primates","volume":"78","author":"Guirakhoo","year":"2004","journal-title":"J. Virol."},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"9998","DOI":"10.1128\/JVI.78.18.9998-10008.2004","article-title":"A single amino acid substitution in the envelope protein of chimeric yellow fever-dengue 1 vaccine virus reduces neurovirulence for suckling mice and viremia\/viscerotropism for monkeys","volume":"78","author":"Guirakhoo","year":"2004","journal-title":"J. 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