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There are no approved vaccines or antiviral drugs to inhibit ZIKV replication. NS2B\u2010NS3 protease (NS2B\u2010NS3 pro), which is essential for viral replication, is a promising molecular target for anti\u2010ZIKV drugs. We conducted a systematic review to identify compounds with promising effects against ZIKV; we discussed their pharmacodynamic and pharmacophoric characteristics. The online search, performed using the PubMed\/MEDLINE and SCOPUS databases, yielded 56 articles; seven relevant studies that reported nine promising compounds with inhibitory activity against ZIKV NS2B\u2010NS3 pro were selected. Of these, five (niclosamide, nitazoxanide, bromocriptine, temoporfin, and novobiocin) are currently available on the market and have been tested for off\u2010label use against ZIKV. The 50% inhibitory concentration values of these compounds for the inhibition of NS2B\u2010NS3 pro ranged at 0.38\u201321.6\u2009\u00b5M; most compounds exhibited noncompetitive inhibition (66%). All compounds that could inhibit the NS2B\u2010NS3 pro complex showed potent in vitro anti\u2010ZIKV activity with a 50% effective concentration ranging 0.024\u201350\u2009\u00b5M. The 50% cytotoxic concentration of the compounds assayed using A549, Vero, and WRL\u201069 cell lines ranged at 0.6\u20131388.02\u2009\u00b5M and the selectivity index was 3.07\u20131698. This review summarizes the most promising antiviral agents against ZIKV that have inhibitory activity against viral proteases.<\/jats:p>","DOI":"10.1002\/jmv.27386","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T18:38:29Z","timestamp":1634063909000},"page":"442-453","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["NS2B\u2010NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review"],"prefix":"10.1002","volume":"94","author":[{"given":"Damiana Ant\u00f4nia de F\u00e1tima","family":"Nunes","sequence":"first","affiliation":[{"name":"Department of Health Sciences, Laboratory of Medical Microbiology, Campus Centro Oeste Dona Lindu Universidade Federal de S\u00e3o Jo\u00e3o del\u2010Rei Divin\u00f3polis Minas Gerais Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe Rocha da Silva","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Laboratory of Medical Microbiology, Campus Centro Oeste Dona Lindu Universidade Federal de S\u00e3o Jo\u00e3o del\u2010Rei Divin\u00f3polis Minas Gerais Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Thamires Dias","family":"da Fonseca","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Laboratory of Medical Microbiology, Campus Centro Oeste Dona Lindu Universidade Federal de S\u00e3o Jo\u00e3o del\u2010Rei Divin\u00f3polis Minas Gerais Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Gustavo","family":"de Lima","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Laboratory of Medical Microbiology, Campus Centro Oeste Dona Lindu Universidade Federal de S\u00e3o Jo\u00e3o del\u2010Rei Divin\u00f3polis Minas Gerais Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waleska Stephanie da Cruz","family":"Nizer","sequence":"additional","affiliation":[{"name":"Department of Health Sciences Carleton University Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaqueline Maria Siqueira","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Laboratory of Medical Microbiology, Campus Centro Oeste Dona Lindu Universidade Federal de S\u00e3o Jo\u00e3o del\u2010Rei Divin\u00f3polis Minas Gerais Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-3186","authenticated-orcid":false,"given":"Jos\u00e9 Carlos","family":"de Magalh\u00e3es","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Cellular Technology, Department of Chemistry, Biotechnology, and Bioprocess Engineering Universidade Federal de S\u00e3o Jo\u00e3o del\u2010Rei Ouro Branco Minas Gerais Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40709-020-00115-4"},{"key":"e_1_2_9_3_1","first-page":"1","article-title":"Recent African strains of Zika virus display higher transmissibility and fetal pathogenicity than Asian strains","volume":"12","author":"Aubry F","year":"2020","journal-title":"Nat Commun"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(52)90042-4"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0006845"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(54)90006-1"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00719"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1602113"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/genomeA.00032-16"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2016.141"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.onehlt.2017.06.001"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.1943"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1590\/0074-02760150192"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag0219"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.17-0322"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.01.056"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jix396"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08302-1"},{"key":"e_1_2_9_19_1","unstructured":"SinanZika virus. 2021. 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