title: Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site.
abstract: Enterovirus 71 (EV71) causes life-threatening diseases with neurological manifestations in young children. However, the treatment of EV71 infections remains an unmet medical need. Idarubicin (IDR) is an anthracycline compound that is used therapeutically for certain types of tumour. In this study, we identified IDR as an EV71 inhibitor, which displayed antiviral potency in the submicromolar range and substantially protected cells from the cytopathic effects and cell death caused by EV71 infections. The antiviral effects extended to several other enterovirus (EV) species, and these effects were independent of cytotoxicity or topoisomerase inhibition. Structure-activity relationship studies indicated the importance of the anthracycline scaffold for anti-EV potency. IDR effectively blocked the synthesis of viral protein and RNA, but not the viral proteolysis processes. Moreover, anthracyclines were demonstrated to suppress EV internal ribosomal entry site (IRES)-mediated translation; conversely, the cellular p53 IRES activity was not sensitive to IDR action. Inhibition of IRES-mediated translation by IDR correlated with the affinity of binding between IDR and the particular IRES. Moreover, IDR impaired binding between the EV71 IRES RNA and hnRNP A1, a known host IRES trans-acting factor. In sum, we have identified a USA FDA-approved anticancer drug with the new indication as a selective EV IRES binder and inhibitor. The finding may also provide leads for the development of novel antiviral therapies directed at the EV IRES RNA.
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Hsin-Yu
authors.initials: HY
authors.lastname: Hou
authors.affiliation: Department of Clinical Pathology, Cheng Hsin General Hospital, Taiwan, ROC.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Lu
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Kuan-Yin
authors.initials: KY
authors.lastname: Wu
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Szu-Hao
authors.initials: SH
authors.lastname: Kung
mesh_terms: D020121:5' Untranslated Regions; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D029821:Enterovirus A, Human / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015255:Idarubicin / Q000737:chemistry / Q000494:pharmacology*; D000067556:Internal Ribosome Entry Sites / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D020121:5' Untranslated Regions; D000998:Antiviral Agents; D000067556:Internal Ribosome Entry Sites; D014764:Viral Proteins; D015255:Idarubicin