title: Efficacy of delayed treatment with ST-246 given orally against systemic orthopoxvirus infections in mice.
abstract: ST-246 was evaluated for activity against cowpox virus (CV), vaccinia virus (VV), and ectromelia virus (ECTV) and had an in vitro 50% effective concentration (EC50) of 0.48 microM against CV, 0.05 microM against VV, and 0.07 microM against ECTV. The selectivity indices were >208 and >2,000 for CV and VV, respectively. The in vitro antiviral activity of ST-246 was significantly greater than that of cidofovir, which had an EC50 of 41.1 microM against CV and 29.2 microM against VV, with selectivity indices of >7 and >10, respectively. ST-246 administered once daily by oral gavage to mice infected intranasally with CV beginning 4 h or delayed until 72 h postinoculation was highly effective when given for a 14-day duration using 100, 30, or 10 mg/kg of body weight. When 100 mg/kg of ST-246 was administered to VV-infected mice, a duration of 5 days was sufficient to significantly reduce mortality even when treatment was delayed 24 h postinoculation. Viral replication in liver, spleen, and kidney, but not lung, of CV- or VV-infected mice was reduced by ST-246 compared to levels for vehicle-treated mice. When 100 mg/kg of ST-246 was given once daily to mice infected by the intranasal route with ECTV, treatment for 10 days prevented mortality even when treatment was delayed up to 72 h after viral inoculation. Viral replication in target organs of ECTV-infected mice was also reduced.
authors.affiliation: University of Alabama at Birmingham, School of Medicine, Department of Pediatrics, 128 Children's Harbor Building, 1600 6th Avenue South, Birmingham, AL 35233-1711, USA. dquenell@uab.edu
authors.forename: Debra C
authors.initials: DC
authors.lastname: Quenelle
authors.forename: R M L
authors.initials: RM
authors.lastname: Buller
authors.forename: Scott
authors.initials: S
authors.lastname: Parker
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Keith
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D007211:Indoles / Q000008:administration & dosage*; D054833:Isoindoles; D051379:Mice; D009928:Organ Specificity; D018155:Orthopoxvirus / Q000187:drug effects* / Q000502:physiology; D011213:Poxviridae Infections / Q000188:drug therapy*; D013997:Time Factors; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects; D010797:Phthalimides
chemical_list: D001549:Benzamides; D007211:Indoles; D054833:Isoindoles; C505045:tecovirimat; D010797:Phthalimides