title: Treatment of lethal Ebola virus infection in mice with a single dose of an S-adenosyl-L-homocysteine hydrolase inhibitor.
abstract: Ebola Zaire virus causes lethal hemorrhagic fever in humans, for which there is no effective treatment. A variety of adenosine analogues inhibit the replication of Ebola virus in vitro, probably by blocking the cellular enzyme, S-adenosyl-L-homocysteine hydrolase, thereby indirectly limiting methylation of the 5' cap of viral messenger RNA. We previously observed that adult, immunocompetent mice treated thrice daily for 9 days with 2.2-20 mg/kg of an adenosine analogue, carbocyclic 3-deazaadenosine, were protected against lethal Ebola virus challenge. We now report that a single inoculation of 80 mg/kg or less of the same substance, or of 1 mg/kg or less of another analogue, 3-deazaneplanocin A, provides equal or better protection, without causing acute toxicity. One dose of drug given on the first or second day after virus infection reduced peak viremia more than 1000-fold, compared with mock-treated controls, and resulted in survival of most or all animals. Therapy was less effective when administered on the day of challenge, or on the third day postinfection. Single or multiple doses of the same medications suppressed Ebola replication in severe combined immunodeficient mice, but even daily treatment for 15 consecutive days did not eliminate the infection.
authors.affiliation: Department of Viral Therapeutics, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702-5011, USA. bray@ncifcrf.gov
authors.forename: M
authors.initials: M
authors.lastname: Bray
authors.forename: J
authors.initials: J
authors.lastname: Driscoll
authors.forename: J W
authors.initials: JW
authors.lastname: Huggins
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity; D043383:Adenosylhomocysteinase; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D029043:Ebolavirus / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy*; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D014372:Tubercidin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; C048460:3-deazaneplanocin; C034072:carbocyclic 3-deazaadenosine; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D014372:Tubercidin