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

Kyungjin Lee,Seong-Jun Kim,Chonsaeng Kim,Sungchan Cho,Dong-Eun Kim,Kyoung-Soon Jang

doi:10.18632/oncotarget.23258

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.

Highlights

Enteroviruses belong to the Picornaviridae family, which is characterized by a single stranded positive-sense RNA genome with about 7500-8000 nucleotides, and have been emerged as the major causative agents of various human diseases
Gemcitabine is known to have an inhibitory activity on the pyrimidine biosynthesis
In this study we sought to examine if the anti-enteroviral activity of gemcitabine is associated with the modulation of pyrimidine biosynthesis and innate immunity

Summary

Introduction

Enteroviruses belong to the Picornaviridae family, which is characterized by a single stranded positive-sense RNA genome with about 7500-8000 nucleotides, and have been emerged as the major causative agents of various human diseases. Broad-spectrum antiviral drugs are necessary to efficiently control various viral infections. In another aspect ineffectiveness of conventional enzymetargeting drugs due to the rapid development of resistant mutants is another hurdle we need to tackle. One is targeting host cellular factor that is essentially required for the viral life cycle. This strategy would have a low potential of producing resistant viruses, but undesirable side effects could be accompanied. Wang et al identified a broad-spectrum antiviral compound (Brequinar) targeting DHODH, a key enzyme of the pyrimidine biosynthetic pathway, and subsequently inducing innate immune response [10]

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