Antiherpesvirus activities of two novel 4'-thiothymidine derivatives, KAY-2-41 and KAH-39-149, are dependent on viral and cellular thymidine kinases.

نویسندگان

  • Natacha Coen
  • Sophie Duraffour
  • Kazuhiro Haraguchi
  • Jan Balzarini
  • Joost J van den Oord
  • Robert Snoeck
  • Graciela Andrei
چکیده

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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Anti - herpesvirus Activity of Two Novel 4 ’ - Thiothymidine Derivatives KAY - 2 - 41 and KAH - 39 - 149 is 1 dependent on viral and cellular thymidine

24 The emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily 25 in immunocompromised patients. Furthermore, effective antiviral therapy against gammaherpesvirus26 associated diseases is lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, 27 with different spectrum of antiviral activity compared to reference anti-...

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عنوان ژورنال:
  • Antimicrobial agents and chemotherapy

دوره 58 8  شماره 

صفحات  -

تاریخ انتشار 2014