Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-020-65152-4
Title: Drug repurposing of pyrimidine analogs as potent antiviral compounds against human enterovirus A71 infection with potential clinical applications
Authors: Sun, J
Yogarajah, T 
Lee, RCH 
Kaur, P 
Inoue, M 
Tan, YW 
Chu, JJH 
Issue Date: 1-Dec-2020
Publisher: Nature Research
Citation: Sun, J, Yogarajah, T, Lee, RCH, Kaur, P, Inoue, M, Tan, YW, Chu, JJH (2020-12-01). Drug repurposing of pyrimidine analogs as potent antiviral compounds against human enterovirus A71 infection with potential clinical applications. Scientific Reports 10 (1) : 8159-. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-020-65152-4
Abstract: © 2020, The Author(s). Enterovirus A71 (EV-A71) is one of the aetiological agents for the hand, foot and mouth disease (HFMD) in young children and a potential cause of neurological complications in afflicted patients. Since its discovery in 1969, there remains no approved antiviral for EV-A71 and other HFMD-causing enteroviruses. We set out to address the lack of therapeutics against EV-A71 by screening an FDA-approved drug library and found an enrichment of hits including pyrimidine antimetabolite, gemcitabine which showed 90.2% of inhibition on EV-A71 infection. Gemcitabine and other nucleoside analogs, LY2334737 and sofosbuvir inhibition of EV-A71 infection were disclosed using molecular and proteomic quantification, and in vitro and in vivo efficacy evaluation. Gemcitabine displayed a significant reduction of infectious EV-A71 titres by 2.5 logs PFU/mL and was shown to target the early stage of EV-A71 viral RNA and viral protein synthesis process especially via inhibition of the RNA dependent RNA polymerase. In addition, the drug combination study of gemcitabine’s synergistic effects with interferon-β at 1:1 and 1:2 ratio enhanced inhibition against EV-A71 replication. Since gemcitabine is known to metabolize rapidly in vivo, other nucleoside analogs, LY2334737 and sofosbuvir conferred protection in mice against lethal EV-A71 challenge by potentially reducing the death rate, viral titers as well on virus-induced pathology in the limb muscle tissue of mice. Additionally, we found that gemcitabine is competent to inhibit other positive-sense RNA viruses of the Flaviviridae and Togaviridae family. Overall, these drugs provide new insights into targeting viral factors as a broad-spectrum antiviral strategy with potential therapeutic value for future development and are worthy of potential clinical application.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/170664
ISSN: 20452322
DOI: 10.1038/s41598-020-65152-4
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