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Nanoparticular inhibitors of flavivirus proteases from Zika, West Nile and Dengue virus are cell-permeable antivirals

Viral 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 infection...

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Main Authors: Schroeder, Barbara (Author) , Demirel, Peter (Author) , Fischer, Christina (Author) , Masri, Enaam (Author) , Kallis, Stephanie (Author) , Redl, Lisa (Author) , Rudolf, Thomas (Author) , Bergemann, Silke (Author) , Arkona, Christoph (Author) , Nitsche, Christoph (Author) , Bartenschlager, Ralf (Author) , Rademann, Jörg (Author)
Format: Article (Journal)
Language:English
Published: November 29, 2021
In: ACS medicinal chemistry letters
Year: 2021, Volume: 12, Issue: 12, Pages: 1955-1961
ISSN:1948-5875
DOI:10.1021/acsmedchemlett.1c00515
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1021/acsmedchemlett.1c00515
Verlag, lizenzpflichtig, Volltext: https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00515
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Author Notes:Barbara Schroeder, Peter Demirel, Christina Fischer, Enaam Masri, Stephanie Kallis, Lisa Redl, Thomas Rudolf, Silke Bergemann, Christoph Arkona, Christoph Nitsche, Ralf Bartenschlager, and Jörg Rademann
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Summary:Viral 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.
Item Description:Gesehen am 22.04.2022
Physical Description:Online Resource
ISSN:1948-5875
DOI:10.1021/acsmedchemlett.1c00515

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