Gemcitabine, a broad-spectrum antiviral drug, suppresses enterovirus infections through innate immunity induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion

Abstract

Gemcitabine, an anti-cancer chemotherapy drug, has additionally shown the antiviral activity against a broad range of viruses and we also have previously reported its synergistic antiviral activity with ribavirin against enteroviruses. As a cytidine analog, gemcitabine has been reported to have an inhibitory activity on the pyrimidine biosynthesis. In addition, a few inhibitors of the pyrimidine biosynthesis have shown to induce the innate immunity in a yet-to-be-determined manner and inhibit the virus infection. Thus, we also investigated whether the anti-enteroviral activity of gemcitabine is mediated by innate immunity, induction of which is related with the inhibition of the pyrimidine synthesis. In this study, we found that the addition of exogenous cytidine, uridine and uridine mono-phosphate (UMP) effectively reversed the antiviral activity of gemcitabine in enterovirus-infected as well as enteroviral replicon-harboring cells, demonstrating gemcitabine’s targeting of the salvage pathway. Moreover, the expression of several interferon (IFN)-stimulated genes (ISGs) was significantly induced by the treatment of gemcitabine, which was also suppressed by the co-treatment with cytidine. These results suggest that the antiviral activity of gemcitabine involves ISGs induced by the inhibition of the pyrimidine biosynthesis.

Novel activities of safe-in-human broad-spectrum antiviral agents

“…We also confirmed previously reported activities of chloroquine against CHIKV and ZIKV, mycophenolic acid against CHIKV and RRV, fluoxetine, pirlindole and dibucaine against EV1, BCX4430, lopinavir and hydroxichloroquine against ZIKV, as well as gemcitabine against EV1, FLUAV, ZIKV and HSV-1 (Cao et al, 2017;Delogu and de Lamballerie, 2011;Delvecchio et al, 2016;Denisova et al, 2012;Julander et al, 2017;Kang et al, 2015;Khan et al, 2011;Kuivanen et al, 2017;Lee et al, 2017;Soderholm et al, 2016;Ulferts et al, 2016;Yuan et al, 2017) (Fig. 4).…”

Gemcitabine and Nucleos(t)ide Synthesis Inhibitors Are Broad-Spectrum Antiviral Drugs that Activate Innate Immunity

“…Importantly, the activation of ISGs was well-correlated with the inhibition of pyrimidine biosynthesis, suggesting a link between pyrimidine biosynthesis and innate immunity. Similar phenomena in terms of ISG activation have been previously reported with a few compounds out of several purine or pyrimidine biosynthesis inhibitors that had antiviral activity, as summarized in Table 2 [ 6 , 10 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

“…Most studies regarding the antiviral activity of gemcitabine lack experimental evidence of the mode of action. However, our group has recently reported that gemcitabine had an anti-EV effect by targeting the salvage pathway of pyrimidine biosynthesis [ 23 ]. Moreover, gemcitabine strongly induced the expression of several ISGs including CXCL10, IRF7, IRF9, IFIT1, and DDX58, which were the major effectors in the innate immunity that defended the host against the virus infection.…”

Drug repurposing for breast cancer therapy: Old weapon for new battle

“…Gemcitabine was primarily manufactured in 1980 by Larry Hertel's group at Eli Lilly and Company to be used as an anti-viral drug against enteroviruses [Coxsackievirus B3 (CVB3)]. The drug was also used against CVB3, EV71, human rhinoviruses (HRVs), human immunodeficiency virus (HIV), hepatitis C virus (HCV), poliovirus, influenza virus, ZIKV and MERS-CoV [104,105]. It was then pre-clinically tested for its anti-tumour attribute.…”