{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T13:57:38Z","timestamp":1769608658955,"version":"3.49.0"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2014,8,1]],"date-time":"2014-08-01T00:00:00Z","timestamp":1406851200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>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<jats:italic>in vitro<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1128\/aac.02825-14","type":"journal-article","created":{"date-parts":[[2014,5,13]],"date-time":"2014-05-13T08:07:32Z","timestamp":1399968452000},"page":"4328-4340","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":20,"title":["Antiherpesvirus Activities of Two Novel 4\u2032-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases"],"prefix":"10.1128","volume":"58","author":[{"given":"Natacha","family":"Coen","sequence":"first","affiliation":[{"name":"Rega Institute for Medical Research, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Duraffour","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Haraguchi","sequence":"additional","affiliation":[{"name":"Nihon Pharmaceutical University, Inamachi, Kita-adachi-gun, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Balzarini","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost J.","family":"van den Oord","sequence":"additional","affiliation":[{"name":"Laboratory of Translational Cell and Tissue Research, University Hospitals Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Snoeck","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graciela","family":"Andrei","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-2277.2012.01485.x"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0001-2815.2004.00227.x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2010.07.008"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/j.1399-0012.1995.tb00297.x","article-title":"Antiviral prophylaxis and the Epstein Barr virus-related post-transplant lymphoproliferative disorder","volume":"9","author":"Davis CL","year":"1995","unstructured":"DavisCLHarrisonKLMcVicarJPForgPJBronnerMPMarshCL. 1995. 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