title: KAY-2-41, a novel nucleoside analogue inhibitor of orthopoxviruses in vitro and in vivo.
abstract: The availability of adequate treatments for poxvirus infections would be valuable not only for human use but also for veterinary use. In the search for novel antiviral agents, a 1'-methyl-substituted 4'-thiothymidine nucleoside, designated KAY-2-41, emerged as an efficient inhibitor of poxviruses. In vitro, KAY-2-41 was active in the micromolar range against orthopoxviruses (OPVs) and against the parapoxvirus orf. The compound preserved its antiviral potency against OPVs resistant to the reference molecule cidofovir. KAY-2-41 had no noticeable toxicity on confluent monolayers, but a cytostatic effect was seen on growing cells. Genotyping of vaccinia virus (VACV), cowpox virus, and camelpox virus selected for resistance to KAY-2-41 revealed a nucleotide deletion(s) close to the ATP binding site or a nucleotide substitution close to the substrate binding site in the viral thymidine kinase (TK; J2R) gene. These mutations resulted in low levels of resistance to KAY-2-41 ranging from 2.7- to 6.0-fold and cross-resistance to 5-bromo-2'-deoxyuridine (5-BrdU) but not to cidofovir. The antiviral effect of KAY-2-41 relied, at least in part, on activation (phosphorylation) by the viral TK, as shown through enzymatic assays. The compound protected animals from disease and mortality after a lethal challenge with VACV, reduced viral loads in the serum, and abolished virus replication in tissues. In conclusion, KAY-2-41 is a promising nucleoside analogue for the treatment of poxvirus-induced diseases. Our findings warrant the evaluation of additional 1'-carbon-substituted 4'-thiothymidine derivatives as broad-spectrum antiviral agents, since this molecule also showed antiviral potency against herpes simplex virus 1 in earlier studies.
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Duraffour
authors.forename: Robert
authors.initials: R
authors.lastname: Drillien
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haraguchi
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Dimitri
authors.initials: D
authors.lastname: Topalis
authors.forename: Joost J
authors.initials: JJ
authors.lastname: van den Oord
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D015608:Cowpox virus / Q000187:drug effects / Q000235:genetics; D005838:Genotype; D015394:Molecular Structure; D018155:Orthopoxvirus / Q000187:drug effects* / Q000235:genetics; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014616:Vaccinia virus / Q000187:drug effects / Q000235:genetics
chemical_list: D000998:Antiviral Agents; C000600961:KAY-2-41; D013876:Thiophenes; D013936:Thymidine