Nanoparticular Inhibitors of Flavivirus Proteases from Zika, West Nile and Dengue Virus Are Cell-Permeable Antivirals
Autor: | Enaam Masri, Peter Demirel, Stephanie Kallis, Christina Fischer, Silke Bergemann, Christoph Nitsche, Ralf Bartenschlager, Jörg Rademann, Thomas Rudolf, Christoph Arkona, Barbara Schroeder, Lisa Redl |
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Rok vydání: | 2021 |
Předmět: |
Drug
Proteases viruses media_common.quotation_subject Hepatitis C virus Cell macromolecular substances Dengue virus 010402 general chemistry medicine.disease_cause 01 natural sciences Biochemistry 03 medical and health sciences Drug Discovery medicine 030304 developmental biology media_common chemistry.chemical_classification 0303 health sciences biology Organic Chemistry biology.organism_classification Virology 0104 chemical sciences 3. Good health Flavivirus medicine.anatomical_structure Enzyme Viral protease chemistry |
Zdroj: | ACS Med Chem Lett |
ISSN: | 1948-5875 |
Popis: | [Image: see text] 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. |
Databáze: | OpenAIRE |
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