Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections.
We assessed the activities of 24 different antiviral compounds against smallpox (two strains of variola major and one of variola minor), monkeypox, vaccinia and cowpox viruses by a neutral red uptake assay. To establish assay parameters, we examined viral replication and its inhibition at various times postinfection and at several multiplicities of infection. Drugs were selected to target a range of functions involved in viral replication. Eight compounds (cidofovir, cyclic HPMPC (cHPMPC), HPMPA, ribavirin, tiazofurin, carbocyclic 3-deazaadenosine, 3-deazaneplanocin A and DFBA (1-(2,4-difluorobenzyloxy)adenosine perchlorate)-a derivative of adenosine N1-oxide) inhibited the replication of all three variola strains and the other orthopoxviruses at drug concentrations within a pharmacologically achievable range. Two others (methisazone and bis-POM-PMEA) showed a lesser degree of antiviral effect, while the remainder were inactive. To examine possible naturally occurring drug resistance among a large number of variola isolates obtained from different geographical regions and at different times, we examined the sensitivity of 35 different strains of variola as well as other orthopoxviruses to a subset of three of the most active compounds: cidofovir, cHPMPC, and ribavirin. Preliminary data indicate that nearly all isolates appear to have similar drug sensitivities. These findings are currently being verified and expanded.
Baker
Robert O
RO
Department of Viral Therapeutics, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702-5011, USA. robert.baker@det.amedd.army.army.mil
Bray
Mike
M
Huggins
John W
JW
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D008826:Microbial Sensitivity Tests; D008993:Monkeypox virus / Q000187:drug effects* / Q000254:growth & development; D009499:Neutral Red / Q000378:metabolism; D018155:Orthopoxvirus / Q000187:drug effects* / Q000254:growth & development; D011213:Poxviridae Infections / Q000188:drug therapy / Q000821:virology*; D012901:Variola virus / Q000187:drug effects* / Q000254:growth & development; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D009499:Neutral Red