Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 12, Issue 12, Pages 1955-1961Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00515
Keywords
Flaviviral protease inhibitors; peptidomimetics; cell-penetrating; nanoparticular inhibitors; multivalency
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB 765, SFB 1349, Ra895-11]
- Australian National University, Canberra
- DAAD
- Australian Research Council [DE190100015]
- Freie Universitat Berlin
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Viral proteases are crucial in virus replication, but there is still no antiviral therapy available for flaviviral infections. Nanoparticular antivirals, such as peptide-dextran conjugates, show promise in inhibiting viral replication at nontoxic concentrations and could be a new strategy for developing broad-spectrum antiflaviviral drugs.
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 broadspectrum antiflaviviral drugs.
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