Antiviral drug therapy of filovirus infections: S-adenosylhomocysteine hydrolase inhibitors inhibit Ebola virus in vitro and in a lethal mouse model

Abstract

Ebola (subtype Zaire) viral replication was inhibited in vitro by a series of nine nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase, an important target for antiviral drug development. Adult BALB/c mice lethally infected with mouse-adapted Ebola virus die 5-7 days after infection. Treatment initiated on day 0 or 1 resulted in dose-dependent protection, with mortality completely prevented at doses ≥0.7 mg/kg every 8 h. There was significant protection (90%) when treatment was begun on day 2, at which time, the liver had an average titer of 3 x 105 pfu/g virus and the spleen had 2 x 106 pfu/g. Treatment with 2.2 mg/kg initiated on day 3, when the liver had an average titer of 2 x 107 pfu/g virus and the spleen had 2 x 108 pfu/g, resulted in 40% survival. As reported here, Carbocyclic 3- deazaadenosine is the first compound demonstrated to cure animals from this otherwise lethal Ebola virus infection.