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Research Project: Viral Ecology of Henipaviruses in Endemic Settings and Intervention Strategies to Prevent their Spread to Domestic Animals

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Title: Delayed low-dose oral administration of 4'-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease

Author
item DAVIES, KATHERINE - Oak Ridge Institute For Science And Education (ORISE)
item SPENGLER, JESSICA - Centers For Disease Control And Prevention (CDC) - United States
item WESTOVER, JONNA - Utah State University
item BAILEY, KEVIN - Utah State University
item WELCH, STEPHEN - Centers For Disease Control And Prevention (CDC) - United States
item AIDA-FICKEN, VIRGINIA - Centers For Disease Control And Prevention (CDC) - United States
item BLUEMLING, GREGORY - Emory University
item BOARDMAN, KRISTEN - Utah State University
item WASSON, SAMANTHA - Utah State University
item MAO, SHULI - Emory University
item KUIPER, DAMIEN - Emory University
item HAGER, MICHAEL - Emory University
item SAINDANE, MANOHAR - Emory University
item ANDREWS, MEGHAN - Emory University
item KRUEGER, REBECCA - Emory University
item STICHER, ZACHARY - Emory University
item JUNG, KIE HOON - Utah State University
item CHATTERJEE, PAYEL - Centers For Disease Control And Prevention (CDC) - United States
item SHRIVASTAVA-RANJAN, PUNYA - Centers For Disease Control And Prevention (CDC) - United States
item LO, MICHAEL - Centers For Disease Control And Prevention (CDC) - United States
item COLEMAN-MCCRAY, JOANN - Centers For Disease Control And Prevention (CDC) - United States
item SORVILLO, TERESA - Centers For Disease Control And Prevention (CDC) - United States
item GENZER, SARAH - Centers For Disease Control And Prevention (CDC) - United States
item SCHOLTE, FLORINE - Centers For Disease Control And Prevention (CDC) - United States
item KELLY, JAMIE - Centers For Disease Control And Prevention (CDC) - United States
item JENKS, M. HARLEY - Centers For Disease Control And Prevention (CDC) - United States
item MCMULLAN, LAURA - Centers For Disease Control And Prevention (CDC) - United States
item ALBARINO, CESAR - Centers For Disease Control And Prevention (CDC) - United States
item MONTGOMERY, JOEL - Centers For Disease Control And Prevention (CDC) - United States
item PAINTER, GEORGE - Emory University
item NATCHUS, MICHAEL - Emory University
item KOLYKHALOV, ALEXANDER - Emory University
item GOWEN, BRIAN - Utah State University
item SPIROPOULOU, CHRISTINA - Centers For Disease Control And Prevention (CDC) - United States
item FLINT, MIKE - Centers For Disease Control And Prevention (CDC) - United States

Submitted to: Science Translational Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/31/2024
Publication Date: 11/20/2024
Citation: Davies, K.A., Spengler, J.R., Westover, J.B., Bailey, K.W., Welch, S.R., Aida-Ficken, V., Bluemling, G.R., Boardman, K.M., Wasson, S.R., Mao, S., Kuiper, D.L., Hager, M.W., Saindane, M.T., Andrews, M.K., Krueger, R.E., Sticher, Z.M., Jung, K., Chatterjee, P., Shrivastava-Ranjan, P., Lo, M.K., Coleman-Mccray, J.D., Sorvillo, T.E., Genzer, S.C., Scholte, F.E., Kelly, J.A., Jenks, M., Mcmullan, L.K., Albarino, C.G., Montgomery, J.M., Painter, G.R., Natchus, M.G., Kolykhalov, A.A., Gowen, B.B., Spiropoulou, C.F., Flint, M. 2024. Delayed low-dose oral administration of 4'-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease. Science Translational Medicine. 16(774). Article eado7034. https://doi.org/10.1126/scitranslmed.ado7034.
DOI: https://doi.org/10.1126/scitranslmed.ado7034

Interpretive Summary: This paper describes the use of an oral antiviral drug for the treatment of arenaviruses. This drug is being explored as a potential treatment for a number of viruses that are unrelated but cause similar disease presentation referred to as viral hemorrhagic fevers.

Technical Abstract: Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4'-fluorouridine (4'-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4'-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4'-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4'-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4'-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4'-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.