title: Increased susceptibility of Cantagalo virus to the antiviral effect of ST-246®.
abstract: Cantagalo virus (CTGV) is the etiologic agent of a pustular disease in dairy cows and dairy workers in Brazil with important economical and occupational impacts. Nevertheless, no antiviral therapy is currently available. ST-246 is a potent inhibitor of orthopoxvirus egress from cells and has proved its efficacy in cell culture and in animal models. In this work, we evaluated the effect of ST-246 on CTGV replication. Plaque reduction assays indicated that CTGV is 6-38 times more susceptible to the drug than VACV-WR and cowpox virus, respectively, with an EC50 of 0.0086μM and a selective index of >11,600. The analysis of β-gal activity expressed by recombinant viruses in the presence of ST-246 confirmed these results. In addition, ST-246 had a greater effect on the reduction of CTGV spread in comet tail assays and on the production of extracellular virus relative to VACV-WR. Infection of mice with CTGV by tail scarification generated primary lesions at the site of scarification that appeared less severe than those induced by VACV-WR. Animals infected with CTGV and treated with ST-246 at 100mg/kg for 5days did not develop primary lesions and virus yields were inhibited by nearly 98%. In contrast, primary lesions induced by VACV-WR were not affected by ST-246. The analysis of F13 (p37) protein from CTGV revealed a unique substitution in residue 217 (D217N) not found in other orthopoxviruses. Construction of recombinant VACV-WR containing the D217N polymorphism did not lead to an increase in the susceptibility to ST-246. Therefore, it is still unknown why CTGV is more susceptible to the antiviral effects of ST-246 compared to VACV-WR. Nonetheless, our data demonstrates that ST-246 is a potent inhibitor of CTGV replication that should be further evaluated as a promising anti-CTGV therapy.
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil.
authors.forename: Élida
authors.initials: É
authors.lastname: Santos-Fernandes
authors.forename: Cristiana O
authors.initials: CO
authors.lastname: Beltrame
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Byrd
authors.forename: Kara B
authors.initials: KB
authors.lastname: Cardwell
authors.forename: Laila C
authors.initials: LC
authors.lastname: Schnellrath
authors.forename: Maria Luiza G
authors.initials: ML
authors.lastname: Medaglia
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Hruby
authors.forename: Robert
authors.initials: R
authors.lastname: Jordan
authors.forename: Clarissa R
authors.initials: CR
authors.lastname: Damaso
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002417:Cattle; D002418:Cattle Diseases / Q000821:virology*; D005260:Female; D054833:Isoindoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D018155:Orthopoxvirus / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011213:Poxviridae Infections / Q000188:drug therapy / Q000662:veterinary*; D016415:Sequence Alignment; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects; D010797:Phthalimides
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; D014764:Viral Proteins; C505045:tecovirimat; D010797:Phthalimides