Drug repurposing of pyrimidine analogs as potent antiviral compounds against human enterovirus A71 infection with potential clinical applications.

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.

• Authors: Jialei Sun, Thinesshwary Yogarajah, Regina Ching Hua Lee, Parveen Kaur, Masafumi Inoue, Yong Wah Tan, Justin Jang Hann Chu
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 8159 (05 18 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32424333 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Pyrimidines
• RNA, Viral
• Deoxycytidine
• Gemcitabine

Topics

• Animals
• Antiviral Agents (administration & dosage, chemistry)
• Deoxycytidine (administration & dosage, analogs & derivatives, chemistry)
• Drug Repositioning
• Enterovirus A, Human (drug effects, genetics, physiology)
• Enterovirus Infections (drug therapy, virology)
• Humans
• Mice
• Mice, Inbred BALB C
• Pyrimidines (administration & dosage, chemistry)
• RNA, Viral (genetics, metabolism)
• Virus Replication (drug effects)
• Gemcitabine