Antiviral drug therapy of filovirus infections: S-adenosylhomocysteine hydrolase inhibitors inhibit Ebola virus in vitro and in a lethal mouse model.
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.
Huggins
J
J
Virology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland 21702-5011, USA. huggins@ncifcrf.gov
Zhang
Z X
ZX
Bray
M
M
D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000627:therapeutic use*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004341:Drug Evaluation; D004353:Drug Evaluation, Preclinical; D029043:Ebolavirus / Q000187:drug effects* / Q000472:pathogenicity; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy / Q000821:virology; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008099:Liver / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000821:virology; D013997:Time Factors; D014372:Tubercidin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014709:Vero Cells