Please use this identifier to cite or link to this item:
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.
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
ISSN: 20452322
DOI: 10.1038/s41598-020-65152-4
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
s41598-020-65152-4.pdfPublished version2.33 MBAdobe PDF




checked on Oct 26, 2020

Page view(s)

checked on Oct 15, 2020


checked on Oct 15, 2020

Google ScholarTM



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.