Efficient lytic induction of kaposi's sarcoma-associated herpesvirus (KSHV) by the anthracyclines

et al. 2015

Antiviral Research

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Enteroviruses are major causative agents of various human diseases, and some of them are currently considered to be an enormous threat to public health. However, no effective therapy is currently available for the treatment of these infections. We identified gemcitabine, a nucleoside-analog drug used for cancer treatment, from a screen of bioactive chemicals as a novel inhibitor of coxsackievirus B3 (CVB3) and enterovirus 71 (EV71). Gemcitabine potently inhibited the proliferation of CVB3 and EV71, as well as the replication of CVB3 and EV71 replicons, in cells with a low micromolar IC50 (1-5 μM). Its strong inhibitory effect was also observed in cells infected with human rhinoviruses, demonstrating broad-spectrum antiviral effects on enteroviruses. Mechanistically, an extensive analysis excluded the involvement of 2C, 3A, IRES-dependent translation, and also that of polyprotein processing in the antiviral effects of gemcitabine. Importantly, gemcitabine in combination with ribavirin, an antiviral drug currently being used against a few RNA viruses, exhibited a synergistic antiviral effect on the replication of CVB3 and EV71 replicons. Consequently, our results clearly demonstrate a new indication for gemcitabine as an effective broad-spectrum inhibitor of enteroviruses and strongly suggest a new therapeutic strategy using gemcitabine alone or in combination with ribavirin for the treatment of various diseases associated with enterovirus infection.

Section: Western Blotting and Rt-pcrmentioning

confidence: 99%

Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses

Kang

et al. 2015

Antiviral Research

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Journal of Medical Virology

“…In infected cells, latent KSHV is difficult to be completely eliminated by current antiviral drugs. 20,21,30 Lytic induction of KSHV represents a promising strategy in countering KSHV-associated tumors.…”

Section: Discussionmentioning

confidence: 99%

vFLIP‐regulated competing endogenous RNA (ceRNA) networks targeting lytic induction for KSHV‐associated malignancies

Sheng

Chen

et al. 2022

Kaposi's sarcoma‐associated herpesvirus (KSHV) causes life‐long latent infection and malignancies, including KS commonly found in AIDS patients. Lytic replication can be induced to kill tumor cells harboring latent KSHV, through viral cytopathic effects and the subsequent antiviral immune responses. Viral FLICE‐inhibitory protein (vFLIP), encoded by KSHV ORF K13, inhibits KSHV lytic reactivation, implying that the competing endogenous RNA (ceRNA) networks regulated by vFLIP can be modulated to induce the lytic reactivation of latent KSHV, a promising strategy for KSHV‐associated malignancies. Here, we performed whole‐transcriptome sequencing to reveal the global landscape of noncoding RNAs and messenger RNAs (mRNAs) in iSLK‐RGB‐BAC16 cells and iSLK‐RGB‐K13 mutant cells. It showed that vFLIP regulated 227 differentially expressed (DE) long non‐coding RNAs (lncRNAs), 57 DE circular RNAs (circRNAs), 20 DE microRNAs (miRNAs), and 1371 DE mRNAs. Enrichment analysis verified that riboflavin metabolism was simultaneously enriched in DE genes related to miRNAs, lncRNAs, and circRNAs. The upregulated hsa‐miR‐378i and hsa‐miR‐3654, and downregulated miR‐4467, miR‐3163, miR‐4451, and miR‐4257 were significantly enriched in the ceRNA complex network, which contained 9 upregulated and 7 downregulated circRNAs, 5 upregulated and 85 downregulated lncRNAs, 5 upregulated and 35 downregulated mRNAs. Finally, we constructed and validated two vFLIP‐regulated ceRNA networks: circRNA hsa_circ_0070049/hsa‐miR‐378i/SPEG/FOXQ1 and lncRNA AL031123.1/hsa‐miR‐378i/SPEG/FOXQ1. Taken together, the two ceRNA networks may mediate KSHV reactivation. These novel findings refreshed the present understanding of ceRNA network in KSHV lytic induction and provided potential therapeutic targets for KSHV‐associated malignancies.

“…Twenty hours after infection, total cell lysates were harvested and analyzed using anti-3C and -β-actin antibodies. RT-PCR was performed as previously described [ 28 ]. For RT-PCR of viral RNA, total cellular RNAs were purified using QIAGEN RNeasy Mini Kit according to manufacturer’s manual.…”

Section: Methodsmentioning

confidence: 99%

Antiviral activity of micafungin against enterovirus 71

Kang

et al. 2016

Virol J

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BackgroundEnterovirus 71 (EV71) is a major causative agent of hand-foot-mouth disease (HFMD) and also causes severe neurological complications, leading to fatality in young children. However, no effective therapy is currently available for the treatment of this infection.MethodsWe identified small-molecule inhibitors of EV71 from a screen of 968 Food and Drug Administration (FDA)-approved drugs, with which clinical application for EV71-associated diseases would be more feasible, using EV71 subgenomic replicon system. Primary hits were extensively evaluated for their antiviral activities in EV71-infected cells.ResultsWe identified micafungin, an echinocandin antifungal drug, as a novel inhibitor of EV71. Micafungin potently inhibits the proliferation of EV71 as well as the replication of EV71 replicon in cells with a low micromolar IC50 (~5 μM). The strong antiviral effect of micafungin on EV71 replicon and the result from time-of-addition experiment demonstrated a targeting of micafungin on virion-independent intracellular process(es) during EV71 infection. Moreover, an extensive analysis excluded the involvement of 2C and 3A proteins, IRES-dependent translation, and also that of polyprotein processing in the antiviral effect of micafungin.ConclusionsOur research revealed a new indication of micafungin as an effective inhibitor of EV71, which is the first case reporting antiviral activity of micafungin, an antifungal drug.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-016-0557-8) contains supplementary material, which is available to authorized users.