Antiherpesvirus Activities of Two Novel 4'-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases
In: Antimicrobial agents and chemotherapy, Jg. 58 (2014), Heft 8, S. 4328-4340
Online
academicJournal
- print, 45 ref
Zugriff:
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.
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Antiherpesvirus Activities of Two Novel 4'-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases
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Autor/in / Beteiligte Person: | COEN, Natacha ; DURAFFOUR, Sophie ; HARAGUCHI, Kazuhiro ; BALZARINI, Jan ; VAN DEN OORD, Joost J ; SNOECK, Robert ; ANDREI, Graciela |
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Zeitschrift: | Antimicrobial agents and chemotherapy, Jg. 58 (2014), Heft 8, S. 4328-4340 |
Veröffentlichung: | Washington, DC: American Society for Microbiology, 2014 |
Medientyp: | academicJournal |
Umfang: | print, 45 ref |
ISSN: | 0066-4804 (print) |
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