Abstract
Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; and potential rescue of amyloid-β (Aβ) induced synaptic impairment. GA was also reported to have activity against Escherichia coli and Staphylococcus aureus. Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. Here we report that GA inhibits Herpes simplex virus type 1 (HSV-1) by inhibition of both fusion and viral protein synthesis. Additionally, we report that GA inhibits human cytomegalovirus (HCMV) genome replication and Zika virus (ZIKV) infection of normal human astrocytes (NHA). We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins including HIV, Ebola virus (EBOV), influenza A virus (IAV) and Epstein Barr virus (EBV). In addition, we show inhibition of a non-enveloped adenovirus. Our experiments suggest that GA inhibits virion entry by blocking the initial fusion event. Data showing inhibition of HSV-1 and CMV replication, when GA is administered post-infection, suggest a possible secondary mechanism targeting protein and DNA synthesis. Thus, in light of the strong effect of GA on viral infection, even after the infection begins, it may potentially be used to treat acute infections (e.g. Coronavirus, EBOV, ZIKV, IAV and measles), and also topically for the successful treatment of active lesions (e.g. HSV-1, HSV-2 and varicella-zoster virus (VZV)).
Highlights
Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba
We show a broad spectrum of fusion inhibition by GA of all three classes of fusion proteins[13] including: pathogenic human enveloped viruses from Class I (ZIKV, HIV, Ebola virus (EBOV), and influenza A virus (IAV)), Class II (Venezuelan equine encephalitis virus (VEEV) and Semliki Forest virus (SFV)), and Class III (vesicular stomatitis virus (VSV) and Epstein Barr virus (EBV))
The toxicity EC50 of GA on HEp-2 cells in MEM supplemented with 1% fetal bovine serum (FBS) was 27.63 ± 2.21 μM (Fig. S1A) or 63.5 ± 3.2 μM (Fig. S1B) on cells supplemented with 5% FBS
Summary
Ginkgolic acids (GA) are alkylphenol constituents of the leaves and fruits of Ginkgo biloba. GA was reported to have activity against Escherichia coli and Staphylococcus aureus Several mechanisms for this activity have been suggested including: SUMOylation inhibition; blocking formation of the E1-SUMO intermediate; inhibition of fatty acid synthase; non-specific SIRT inhibition; and activation of protein phosphatase type-2C. GA has shown pleiotropic effects in vitro, including: antitumor effects through inhibition of lipogenesis; decreased expression of invasion associated proteins through AMPK activation; potential rescue of amyloid-β (Aβ) induced synaptic impairment; and inhibition of HIV protease activity as well as HIV viral replication[4,5,6,7]. Several ways in which GA works have been suggested including by SUMOylation inhibition activity; blocking formation of the E1-SUMO intermediate[9]; inhibition of fatty acid synthase[10]; non-specific SIRT inhibition[11]; and activation of protein phosphatase type-2C12. Our experiments suggest that GA inhibits viral entry by blocking the initial fusion event
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