Nanoparticular Inhibitors of Flavivirus Proteases from Zika, West Nile and Dengue Virus Are Cell-Permeable Antivirals

dc.contributor.authorSchroeder, Barbara
dc.contributor.authorDemirel, Peter
dc.contributor.authorFischer, Christina
dc.contributor.authorMasri, Enaam
dc.contributor.authorKallis, Stephanie
dc.contributor.authorRedl, Lisa
dc.contributor.authorRudolf, Thomas
dc.contributor.authorBergemann, Silke
dc.contributor.authorArkona, Christoph
dc.contributor.authorNitsche, Christoph
dc.contributor.authorBartenschlager, Ralf
dc.contributor.authorRademann, Jörg
dc.date.accessioned2022-08-02T07:01:37Z
dc.date.issued2021-12-09
dc.description.abstractViral proteases have been established as drug targets in several viral diseases including human immunodeficiency virus and hepatitis C virus infections due to the essential role of these enzymes in virus replication. In contrast, no antiviral therapy is available to date against flaviviral infections including those by Zika virus (ZIKV), West Nile virus (WNV), or dengue virus (DENV). Numerous potent inhibitors of flaviviral proteases have been reported; however, a huge gap remains between the in vitro and intracellular activities, possibly due to low cellular uptake of the charged compounds. Here, we present an alternative, nanoparticular approach to antivirals. Conjugation of peptidomimetic inhibitors and cell-penetrating peptides to dextran yielded chemically defined nanoparticles that were potent inhibitors of flaviviral proteases. Peptide-dextran conjugates inhibited viral replication and infection in cells at nontoxic, low micromolar or even nanomolar concentrations. Thus, nanoparticular antivirals might be alternative starting points for the development of broad-spectrum antiflaviviral drugs.en_AU
dc.description.sponsorshipC.N. thanks the Australian Research Council for a Discovery Early Career Research Award (DE190100015) and the Freie Universität Berlin for a Rising Star fellowship.en_AU
dc.format.mimetypeapplication/pdfen_AU
dc.identifier.issn1948-5875en_AU
dc.identifier.urihttp://hdl.handle.net/1885/270119
dc.language.isoen_AUen_AU
dc.provenancehttps://v2.sherpa.ac.uk/id/publication/7764..."The Accepted Version can be archived in a Non-Commercial Institutional Repository If Required by Funder, If Required by Institution. 12 months embargo " from SHERPA/RoMEO site (as at 2/08/2022).en_AU
dc.publisherAmerican Chemical Societyen_AU
dc.relationhttp://purl.org/au-research/grants/arc/DE190100015en_AU
dc.rights© 2021 American Chemical Societyen_AU
dc.sourceACS medicinal chemistry lettersen_AU
dc.subjectFlaviviral protease inhibitorsen_AU
dc.subjectpeptidomimeticsen_AU
dc.subjectcell-penetratingen_AU
dc.subjectnanoparticular inhibitorsen_AU
dc.subjectmultivalencyen_AU
dc.titleNanoparticular Inhibitors of Flavivirus Proteases from Zika, West Nile and Dengue Virus Are Cell-Permeable Antiviralsen_AU
dc.typeJournal articleen_AU
dcterms.accessRightsOpen Accessen_AU
dcterms.dateAccepted2021
local.bibliographicCitation.issue12en_AU
local.bibliographicCitation.lastpage1961en_AU
local.bibliographicCitation.startpage1955en_AU
local.contributor.affiliationNitsche, C., Research School of Chemistry, The Australian National Universityen_AU
local.contributor.authoremailu5424054@anu.edu.auen_AU
local.contributor.authoruidu5424054en_AU
local.identifier.ariespublicationa383154xPUB23358
local.identifier.citationvolume12en_AU
local.identifier.doi10.1021/acsmedchemlett.1c00515en_AU
local.identifier.uidSubmittedByu5424054en_AU
local.publisher.urlhttp://pubs.acs.org/journal/amclcten_AU
local.type.statusAccepted Versionen_AU

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