Antiviral Drug Therapy of Filovirus Infections: S-Adenosylhomocysteine Hydrolase Inhibitors Inhibit Ebola Virus In Vitro and in a Lethal Mouse Model

• Published in: The Journal of infectious diseases 1999-02, Vol.179 (Supplement-1), p.S240-S247
• Main Authors: Huggins, John, Zhang, Zhen-Xi, Bray, Mike
• Format: Article
• Language: English
• Subjects: Adenosylhomocysteinase; Animals; Antiviral Agents - chemistry; Antiviral Agents - therapeutic use; Antivirals; Cercopithecus aethiops; Disease Models, Animal; Dosage; Drug design; Drug Evaluation; Drug Evaluation, Preclinical; Ebola virus; Ebolavirus - drug effects; Ebolavirus - pathogenicity; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - therapeutic use; Enzymes; Experimental Therapy; Hemorrhagic Fever, Ebola - drug therapy; Hemorrhagic Fever, Ebola - virology; Hydrolases - antagonists & inhibitors; In Vitro Techniques; Infections; Liver; Liver - virology; Mice; Mice, Inbred BALB C; Primates; Spleen - virology; Time Factors; Tubercidin - analogs & derivatives; Tubercidin - therapeutic use; Vero Cells; Viruses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/514316

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 × 105 pfu/g virus and the spleen had 2 × 106 pfu/g. Treatment with 2.2 mg/kg initiated on day 3, when the liver had an average titer of 2 × 107 pfu/g virus and the spleen had 2 × 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.