Diphyllin Shows a Broad-Spectrum Antiviral Activity against Multiple Medically Important Enveloped RNA and DNA Viruses
Michal Štefánik,
Dattatry Shivajirao Bhosale,
Jan Haviernik,
Petra Straková,
Martina Fojtíková,
Lucie Dufková,
Ivana Huvarová,
Jiří Salát,
Jan Bartáček,
Jan Svoboda,
Miloš Sedlák,
Daniel Růžek,
Andrew D. Miller,
Luděk Eyer
Affiliations
Michal Štefánik
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Dattatry Shivajirao Bhosale
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Jan Haviernik
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Petra Straková
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Martina Fojtíková
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Lucie Dufková
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Ivana Huvarová
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Jiří Salát
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Jan Bartáček
Faculty of Chemical Technology, Institute of Organic Chemistry and Technology, University of Pardubice, Studentská 573, CZ-532 10 Pardubice, Czech Republic
Jan Svoboda
Faculty of Chemical Technology, Institute of Organic Chemistry and Technology, University of Pardubice, Studentská 573, CZ-532 10 Pardubice, Czech Republic
Miloš Sedlák
Faculty of Chemical Technology, Institute of Organic Chemistry and Technology, University of Pardubice, Studentská 573, CZ-532 10 Pardubice, Czech Republic
Daniel Růžek
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Andrew D. Miller
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
Luděk Eyer
Laboratory of Emerging Viral Diseases, Veterinary Research Institute, Hudcova 296/70, CZ-621 00 Brno, Czech Republic
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.