Last data update: Dec 02, 2024. (Total: 48272 publications since 2009)
Records 1-2 (of 2 Records) |
Query Trace: Kelly JA[original query] |
---|
Delayed low-dose oral administration of 4'-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease
Welch SR , Spengler JR , Westover JB , Bailey KW , Davies KA , Aida-Ficken V , Bluemling GR , Boardman KM , Wasson SR , Mao S , Kuiper DL , Hager MW , Saindane MT , Andrews MK , Krueger RE , Sticher ZM , Jung KH , Chatterjee P , Shrivastava-Ranjan P , Lo MK , Coleman-McCray JD , Sorvillo TE , Genzer SC , Scholte FEM , Kelly JA , Jenks MH , McMullan LK , Albariño CG , Montgomery JM , Painter GR , Natchus MG , Kolykhalov AA , Gowen BB , Spiropoulou CF , Flint M . Sci Transl Med 2024 16 (774) eado7034 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. |
Identification of a macrocyclic compound targeting the Lassa virus polymerase
Aida-Ficken V , Kelly JA , Chatterjee P , Jenks MH , McMullan LK , Albariño CG , Montgomery JM , Seley-Radtke KL , Spiropoulou CF , Flint M . Antiviral Res 2024 105923 There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC(50) against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase. |
- Page last reviewed:Feb 1, 2024
- Page last updated:Dec 02, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure