Diphyllin Shows a Broad-Spectrum Antiviral Activity against Multiple Medically Important Enveloped RNA and DNA Viruses

Abstract

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.

Antiviral activity of singlet oxygen-photogenerating perylene compounds against SARS-CoV-2: Interaction with the viral envelope and photodynamic virion inactivation

“…For example, HSV-1 enters host cells predominantly via plasma membrane interactions and fusion at the cell surface ( White and Whittaker, 2016 ). On the other hand, the virus–cell fusion machineries of coronaviruses and flaviviruses are strictly based on receptor-mediated endocytosis, followed by lower pH-induced fusion of the viral envelope with the endosomal membrane ( Hu et al., 2017 ; Štefánik et al., 2022 ). Obviously, the perylene-based antiviral effect is independent of these differences in virus–cell entry mechanisms.…”

Arylnaphthalene Lignans with Anti-SARS-CoV-2 and Antiproliferative Activities from the Underground Organs of Linum austriacum and Linum perenne

“…Our results are in good accordance with those of a very recent study that confirmed the anti-SARS-CoV-2 activity (IC 50 , 1.92 μM) and low cytotoxicity (IC 50 value >100 μM) in the Vero E6 host cells for 1. 8 Literature results also show that the antiviral activity of the monoglycoside of 1 against SARS-CoV-2 8 and tick-borne encephalitis virus (TBEV) 9 as well as that of the diglycoside and triglycoside of 1 against the human immunodeficiency virus 1 (HIV-1) 5 was 3.4, 6.3, 13.0, and 62.1 times lower than the antiviral activity of the free aglycone 1, respectively. Due to these results, glycosides of 1 (compounds 5−8) were not isolated from our Linum samples to test their anti-SARS-CoV-2 activity.…”

“…They are effective in vitro antiviral agents at submicromolar concentrations against various viruses, with low toxicity in the host cells used to propagate the viruses (Supporting Table S1). − Compound 1 also presents antiviral activity against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), without expressing any toxicity against the host cells Vero and Vero E6 (both are kidney epithelial cells derived from Cercopithecus aethiops ) …”

Natural Products and Derivatives as Potential Zika virus Inhibitors: A Comprehensive Review

“…Diphyllin is an arylnaphtalide lignan extracted from plants used in the traditional Chinese medicine and exerted antiviral activity against ZIKV (Paraiba 01 strain) in Vero cells (EC 50 = 0.54 μM, CC 50 > 100 μM and SI > 185.19). When tested at concentrations between 12.5 and 25 μM, the viral surface antigen expression was eliminated in Vero cells [ 106 ].…”