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Heparin, a clinical-grade anticoagulant, is shown to protect neural progenitor cells from death following ZIKV infection. Although heparin can be safely used during pregnancy, it retains off-target anticoagulant effects if directly employed against ZIKV infection. In this study, we investigated the effects of chemically modified heparin derivatives with reduced anticoagulant activities. These derivatives were used as experimental probes to explore the structure\u2013activity relationships. Precursor fractions of porcine heparin, obtained during the manufacture of conventional pharmaceutical heparin with decreased anticoagulant activities, were also explored. Interestingly, these modified heparin derivatives and precursor fractions not only prevented cell death but also inhibited the ZIKV replication of infected neural progenitor cells grown as neurospheres. These effects were observed regardless of the specific sulfation position or overall charge. Furthermore, the combination of heparin with Sofosbuvir, an antiviral licensed for the treatment of hepatitis C (HCV) that also belongs to the same Flaviviridae family as ZIKV, showed a synergistic effect. This suggested that a combination therapy approach involving heparin precursors and Sofosbuvir could be a potential strategy for the prevention or treatment of ZIKV infections.<\/jats:p>","DOI":"10.3390\/ph16101385","type":"journal-article","created":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T16:57:06Z","timestamp":1696179426000},"page":"1385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Heparin Precursors with Reduced Anticoagulant Properties Retain Antiviral and Protective Effects That Potentiate the Efficacy of Sofosbuvir against Zika Virus Infection in Human Neural Progenitor Cells"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5396-0740","authenticated-orcid":false,"given":"Isabel","family":"Pagani","sequence":"first","affiliation":[{"name":"Viral Pathogenesis and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Ottoboni","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9913-8568","authenticated-orcid":false,"given":"Paola","family":"Panina-Bordignon","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianvito","family":"Martino","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"},{"name":"School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7241-4526","authenticated-orcid":false,"given":"Guido","family":"Poli","sequence":"additional","affiliation":[{"name":"School of Medicine, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy"},{"name":"Human Immuno-Virology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Systems Biology, ISMIB, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1791-754X","authenticated-orcid":false,"given":"Jeremy E.","family":"Turnbull","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Systems Biology, ISMIB, University of Liverpool, Liverpool L69 7ZB, UK"},{"name":"Department of Life Sciences, Keele University, Keele, Staffs ST5 5BG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9365-5433","authenticated-orcid":false,"given":"Edwin","family":"Yates","sequence":"additional","affiliation":[{"name":"Department of Biochemistry & Systems Biology, ISMIB, University of Liverpool, Liverpool L69 7ZB, UK"},{"name":"Department of Life Sciences, Keele University, Keele, Staffs ST5 5BG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"Vicenzi","sequence":"additional","affiliation":[{"name":"Viral Pathogenesis and Biosafety Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/S0167-5273(16)12001-7","article-title":"Heparin centenary\u2014An ever-young life-saving drug","volume":"212","author":"Torri","year":"2016","journal-title":"Int. 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