carbocyclic-3-deazaadenosine and Disease-Models--Animal

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 > or =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 10(5) pfu/g virus and the spleen had 2 x 10(6) pfu/g. Treatment with 2.2 mg/kg initiated on day 3, when the liver had an average titer of 2 x 10(7) pfu/g virus and the spleen had 2 x 10(8) 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.

Topics: Adenosylhomocysteinase; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation; Drug Evaluation, Preclinical; Ebolavirus; Enzyme Inhibitors; Hemorrhagic Fever, Ebola; Hydrolases; In Vitro Techniques; Liver; Mice; Mice, Inbred BALB C; Spleen; Time Factors; Tubercidin; Vero Cells