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Efficacy of ST-246 versus lethal poxvirus challenge in immunodeficient mice.

Abstract
The threat of smallpox as a bioweapon and the emerging threat of human monkeypox, among other poxviral diseases, highlight the need for effective poxvirus countermeasures. ST-246, which targets the F13L protein in vaccinia virus and its homologs in other orthopoxvirus species, provides full protection from lethal poxviral disease in numerous animal models and seems to be safe in humans. All previous evaluations of ST-246 efficacy have been in immunocompetent animals. However, the risk of severe poxviral disease is greater in immunodeficient hosts. Here we report on the efficacy of ST-246 in preventing or treating lethal poxviral disease in immunodeficient mice. After lethal challenge with the Western Reserve strain of vaccinia, Nude, SCID, and J(H) knockout mice additionally depleted of CD4(+) and CD8(+) T cells were not fully protected by ST-246, although survival was significantly extended. However, CD4(+) T cell deficient, CD8(+) T cell deficient, J(H) knockout, and J(H) knockout mice also deficient for CD4(+) or CD8(+) T cells survived lethal challenge when treated with ST-246 starting on the day of challenge. Delaying treatment until 72 h after infection reduced ST-246 efficacy in some models but provided full protection from lethal challenge in most. These findings suggest that ST-246 may be effective in controlling smallpox or other pathogenic orthopoxviruses in some immunodeficient human populations for whom the vaccine is contraindicated.
AuthorsDouglas W Grosenbach, Aklile Berhanu, David S King, Stacie Mosier, Kevin F Jones, Robert A Jordan, Tove' C Bolken, Dennis E Hruby
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 2 Pg. 838-43 (Jan 12 2010) ISSN: 1091-6490 [Electronic] United States
PMID20080762 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antiviral Agents
  • Benzamides
  • Isoindoles
  • ST-246
Topics
  • Animals
  • Antiviral Agents (therapeutic use)
  • Benzamides (therapeutic use)
  • Humans
  • Isoindoles (therapeutic use)
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Orthopoxvirus (drug effects)
  • Poxviridae (drug effects, pathogenicity)
  • Poxviridae Infections (drug therapy)
  • Treatment Outcome
  • Viral Plaque Assay
  • Virulence

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