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Drug repurposing of pyrimidine analogs as potent antiviral compounds against human enterovirus A71 infection with potential clinical applications.
- Source :
-
Scientific reports [Sci Rep] 2020 May 18; Vol. 10 (1), pp. 8159. Date of Electronic Publication: 2020 May 18. - Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Animals
Antiviral Agents chemistry
Deoxycytidine administration & dosage
Deoxycytidine chemistry
Drug Repositioning
Enterovirus A, Human genetics
Enterovirus A, Human physiology
Enterovirus Infections virology
Humans
Mice
Mice, Inbred BALB C
Pyrimidines chemistry
RNA, Viral genetics
RNA, Viral metabolism
Virus Replication drug effects
Gemcitabine
Antiviral Agents administration & dosage
Deoxycytidine analogs & derivatives
Enterovirus A, Human drug effects
Enterovirus Infections drug therapy
Pyrimidines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 32424333
- Full Text :
- https://doi.org/10.1038/s41598-020-65152-4