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Antiviral Res ; 171: 104597, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31494195

RESUMO

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 (ß-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.


Assuntos
Antivirais/farmacologia , Vírus da Encefalite Equina Venezuelana/efeitos dos fármacos , Encefalomielite Equina Venezuelana/virologia , Ribonucleosídeos/farmacologia , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/química , Antivirais/farmacocinética , Linhagem Celular , Cromatografia Líquida , Modelos Animais de Doenças , Encefalomielite Equina Venezuelana/tratamento farmacológico , Cavalos , Camundongos , Estrutura Molecular , Ribonucleosídeos/administração & dosagem , Ribonucleosídeos/química , Ribonucleosídeos/farmacocinética , Espectrometria de Massas em Tandem , Distribuição Tecidual , Replicação Viral/efeitos dos fármacos
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