The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection

Antiviral Res. 2019 Nov:171:104597. doi: 10.1016/j.antiviral.2019.104597. Epub 2019 Sep 5.

Abstract

The New World alphaviruses Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively) commonly cause a febrile disease that can progress to meningoencephalitis, resulting in significant morbidity and mortality. To address the need for a therapeutic agent for the treatment of Alphavirus infections, we identified and pursued preclinical characterization of a ribonucleoside analog EIDD-1931 (β-D-N4-hydroxycytidine, NHC), which has shown broad activity against alphaviruses in vitro and has a very high genetic barrier for development of resistance. To be truly effective as a therapeutic agent for VEEV infection a drug must penetrate the blood brain barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly achieved in mice after oral dosing. Once in the plasma EIDD-1931 is efficiently distributed into organs, including brain, where it is rapidly converted to its active 5'-triphosphate. EIDD-1931 showed a good safety profile in mice after 7-day repeated dosing with up to 1000 mg/kg/day doses. In mouse model studies, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal infection when therapeutic treatment was started as late as 24 h post-infection, and partial protection was achieved when treatment was delayed for 48 h post-infection. These results support further preclinical development of EIDD-1931 as a potential anti-alphavirus drug.

Keywords: Alphavirus; CNS penetration; Murine model; Ribonucleoside analog; Therapeutic treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacokinetics
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Chromatography, Liquid
  • Disease Models, Animal
  • Encephalitis Virus, Venezuelan Equine / drug effects*
  • Encephalomyelitis, Venezuelan Equine / drug therapy
  • Encephalomyelitis, Venezuelan Equine / virology*
  • Horses
  • Mice
  • Molecular Structure
  • Ribonucleosides / administration & dosage
  • Ribonucleosides / chemistry
  • Ribonucleosides / pharmacokinetics
  • Ribonucleosides / pharmacology*
  • Tandem Mass Spectrometry
  • Tissue Distribution
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Ribonucleosides