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The 2013\u20132015 Zika virus (ZIKV) outbreak in South and Central America has been associated with cases of microcephaly in newborns and Guillain\u2013Barret syndrome. We previously showed that the conjugate gallic acid\u2014Hecate (GA-FALALKALKKALKKLKKALKKAL-CONH2)\u2014is an efficient inhibitor of the hepatitis C virus. Here, we show that the Hecate peptide is degraded in human blood serum into three major metabolites. These metabolites conjugated with gallic acid were synthesized and their effect on ZIKV replication in cultured cells was evaluated. The GA-metabolite 5 (GA-FALALKALKKALKKL-COOH) was the most efficient in inhibiting two ZIKV strains of African and Asian lineage at the stage of both virus entry (virucidal and protective) and replication (post-entry). We also demonstrate that GA-metabolite 5 does not affect cell growth after 7 days of continuous treatment. Thus, this study identifies a new synthetic antiviral compound targeting different steps of ZIKV replication in vitro and with the potential for broad reactivity against other flaviviruses. Our work highlights a promising strategy for the development of new antivirals based on peptide metabolism and bioconjugation.<\/jats:p>","DOI":"10.3390\/molecules28134884","type":"journal-article","created":{"date-parts":[[2023,6,21]],"date-time":"2023-06-21T02:01:33Z","timestamp":1687312893000},"page":"4884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Antiviral Evaluation of New Synthetic Bioconjugates Based on GA-Hecate: A New Class of Antivirals Targeting Different Steps of Zika Virus Replication"],"prefix":"10.3390","volume":"28","author":[{"given":"Paulo Ricardo","family":"da Silva Sanches","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Science, S\u00e3o Paulo State University, Araraquara 14800-903, SP, Brazil"},{"name":"MRC\u2014University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G12 8QQ, UK"},{"name":"Institute of Chemistry, S\u00e3o Paulo State University, Araraquara 14800-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6716-442X","authenticated-orcid":false,"given":"Ricardo","family":"Velazquez","sequence":"additional","affiliation":[{"name":"MRC\u2014University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G12 8QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Nogueira","family":"Batista","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Infectious Diseases, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2355-7907","authenticated-orcid":false,"given":"Bruno Moreira","family":"Carneiro","sequence":"additional","affiliation":[{"name":"School of Health Science, Federal University of Rondon\u00f3polis, Rondon\u00f3polis 78736-900, MT, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cintia","family":"Bittar","sequence":"additional","affiliation":[{"name":"School of Health Science, Federal University of Rondon\u00f3polis, Rondon\u00f3polis 78736-900, MT, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-8740","authenticated-orcid":false,"given":"Giuditta","family":"De Lorenzo","sequence":"additional","affiliation":[{"name":"MRC\u2014University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G12 8QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5693-6148","authenticated-orcid":false,"given":"Paula","family":"Rahal","sequence":"additional","affiliation":[{"name":"Institute of Bioscience, Humanities and Exact Science, S\u00e3o Paulo State University, S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4600-2047","authenticated-orcid":false,"given":"Arvind H.","family":"Patel","sequence":"additional","affiliation":[{"name":"MRC\u2014University of Glasgow Centre for Virus Research, University of Glasgow, Glasgow G12 8QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4767-0904","authenticated-orcid":false,"given":"Eduardo Maffud","family":"Cilli","sequence":"additional","affiliation":[{"name":"Institute of Chemistry, S\u00e3o Paulo State University, Araraquara 14800-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1016\/j.cell.2018.11.028","article-title":"Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis","volume":"175","author":"Shah","year":"2018","journal-title":"Cell"},{"key":"ref_2","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. 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