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

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Painter GR, Bowen RA, Bluemling GR, DeBergh J, Edpuganti V, Gruddanti PR, Guthrie DB, Hager M, Kuiper DL, Lockwood MA, Mitchell DG, Natchus MG, Sticher ZM, Kolykhalov AA

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.

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31494195 [ View in PubMed
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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 (beta-D-N(4)-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 1000mg/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 24h post-infection, and partial protection was achieved when treatment was delayed for 48h post-infection. These results support further preclinical development of EIDD-1931 as a potential anti-alphavirus drug.

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