Diphyllin is a natural arylnaphtalide lignan extracted from tropical plants of particular importance in traditional Chinese medicine. This compound has been described as a potent inhibitor of vacuolar (H+)ATPases and hence of the endosomal acidification process that is required by numerous enveloped viruses to trigger their respective viral infection cascades after entering host cells by receptor-mediated endocytosis. Accordingly, we report here a revised, updated, and improved synthesis of diphyllin, and demonstrate its antiviral activities against a panel of enveloped viruses from Flaviviridae, Phenuiviridae, Rhabdoviridae, and Herpesviridae families. Diphyllin is not cytotoxic for Vero and BHK-21 cells up to 100 μM and exerts a sub-micromolar or low-micromolar antiviral activity against tick-borne encephalitis virus, West Nile virus, Zika virus, Rift Valley fever virus, rabies virus, and herpes-simplex virus type 1. Our study shows that diphyllin is a broad-spectrum host cell-targeting antiviral agent that blocks the replication of multiple phylogenetically unrelated enveloped RNA and DNA viruses. In support of this, we also demonstrate that diphyllin is more than just a vacuolar (H+)ATPase inhibitor but may employ other antiviral mechanisms of action to inhibit the replication cycles of those viruses that do not enter host cells by endocytosis followed by low pH-dependent membrane fusion.
- MeSH
- antigeny virové metabolismus MeSH
- antivirové látky chemická syntéza farmakologie MeSH
- buněčné linie MeSH
- glukosidy farmakologie MeSH
- lignany chemická syntéza farmakologie MeSH
- replikace viru účinky léků MeSH
- vakuolární protonové ATPasy antagonisté a inhibitory MeSH
- viabilita buněk účinky léků MeSH
- viry klasifikace účinky léků metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
G-quadruplexes contribute to the regulation of key molecular processes. Their utilization for antiviral therapy is an emerging field of contemporary research. Here we present comprehensive analyses of the presence and localization of putative G-quadruplex forming sequences (PQS) in all viral genomes currently available in the NCBI database (including subviral agents). The G4Hunter algorithm was applied to a pool of 11,000 accessible viral genomes representing 350 Mbp in total. PQS frequencies differ across evolutionary groups of viruses, and are enriched in repeats, replication origins, 5'UTRs and 3'UTRs. Importantly, PQS presence and localization is connected to viral lifecycles and corresponds to the type of viral infection rather than to nucleic acid type; while viruses routinely causing persistent infections in Metazoa hosts are enriched for PQS, viruses causing acute infections are significantly depleted for PQS. The unique localization of PQS identifies the importance of G-quadruplex-based regulation of viral replication and life cycle, providing a tool for potential therapeutic targeting.
- MeSH
- databáze nukleových kyselin * MeSH
- DNA virů genetika metabolismus MeSH
- G-kvadruplexy * MeSH
- genom virový * MeSH
- lidé MeSH
- virové nemoci * genetika metabolismus MeSH
- viry * genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- Bacteria enzymologie metabolismus růst a vývoj MeSH
- Eukaryota enzymologie metabolismus růst a vývoj MeSH
- houby enzymologie metabolismus růst a vývoj MeSH
- kultivace virů MeSH
- kultivační média MeSH
- mikrobiální genetika MeSH
- teoretické modely MeSH
- viry enzymologie metabolismus růst a vývoj MeSH
- zdravotnické prostředky MeSH
- Publikační typ
- bibliografie MeSH
