title: Antiherpesvirus activities of two novel 4'-thiothymidine derivatives, KAY-2-41 and KAH-39-149, are dependent on viral and cellular thymidine kinases.
abstract: The emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivity in vitro. While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Natacha
authors.initials: N
authors.lastname: Coen
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Duraffour
authors.affiliation: Nihon Pharmaceutical University, Inamachi, Kita-adachi-gun, Saitama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haraguchi
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: Laboratory of Translational Cell and Tissue Research, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Joost J
authors.initials: JJ
authors.lastname: van den Oord
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Leuven, Belgium graciela.andrei@rega.kuleuven.be.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects; D057075:Enzyme Assays; D006367:HeLa Cells; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000254:growth & development; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000254:growth & development; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000254:growth & development; D004854:Herpesvirus 4, Human / Q000187:drug effects / Q000254:growth & development; D054884:Host-Pathogen Interactions; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D013872:Thionucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C000600962:KAH-39-149; C000600961:KAY-2-41; D013872:Thionucleosides; D013876:Thiophenes; D014764:Viral Proteins; C070456:4'-thiothymidine; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine