Treatment of lethal Ebola virus infection in mice with a single dose of anS-adenosyl-L-homocysteine hydrolase inhibitor

Ebola Zaire virus causes lethal hemorrhagic fever in humans, for which ther e is no effective treatment. A variety of adenosine analogues inhibit the r eplication of Ebola virus in vitro, probably by blocking the cellular enzym e, S-adenosyl-L-homocysteine hydrolase, thereby indirectly limiting methyla tion of the 5' cap of viral messenger RNA. We previously observed that adul t, immunocompetent mice treated thrice daily for 9 days with 2.2-20 mg/kg o f an adenosine analogue, carbocyclic 3-deazaadenosine, were protected again st 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 a nalogue, 3-deazaneplanocin A, provides equal or better protection, without causing acute toxicity. One dose of drug given on the first or second day a fter virus infection reduced peak viremia more than 1000-fold, compared wit h mock-treated controls, and resulted in survival of most or all animals. T herapy was less effective when administered on the day of challenge, or on the third day postinfection. Single or multiple doses of the same medicatio ns suppressed Ebola replication in severe combined immunodeficient mice, bu t even daily treatment for 15 consecutive days did not eliminate the infect ion. Published by Elsevier Science B.V.