{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T22:56:25Z","timestamp":1791586585436,"version":"4.3.4"},"reference-count":117,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,3,12]],"date-time":"2019-03-12T00:00:00Z","timestamp":1552348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Epstein\u2013Barr virus (EBV) is a human \u03b3-herpesvirus that infects up to 95% of the adult population. Primary EBV infection usually occurs during childhood and is generally asymptomatic, though the virus can cause infectious mononucleosis in 35\u201350% of the cases when infection occurs later in life. EBV infects mainly B-cells and epithelial cells, establishing latency in resting memory B-cells and possibly also in epithelial cells. EBV is recognized as an oncogenic virus but in immunocompetent hosts, EBV reactivation is controlled by the immune response preventing transformation in vivo. Under immunosuppression, regardless of the cause, the immune system can lose control of EBV replication, which may result in the appearance of neoplasms. The primary malignancies related to EBV are B-cell lymphomas and nasopharyngeal carcinoma, which reflects the primary cell targets of viral infection in vivo. Although a number of antivirals were proven to inhibit EBV replication in vitro, they had limited success in the clinic and to date no antiviral drug has been approved for the treatment of EBV infections. We review here the antiviral drugs that have been evaluated in the clinic to treat EBV infections and discuss novel molecules with anti-EBV activity under investigation as well as new strategies to treat EBV-related diseases.<\/jats:p>","DOI":"10.3390\/molecules24050997","type":"journal-article","created":{"date-parts":[[2019,3,13]],"date-time":"2019-03-13T04:07:37Z","timestamp":1552450057000},"page":"997","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["Novel Therapeutics for Epstein\u2013Barr Virus"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2609-4896","authenticated-orcid":false,"given":"Graciela","family":"Andrei","sequence":"first","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0249-9776","authenticated-orcid":false,"given":"Erika","family":"Trompet","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Snoeck","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1542\/peds.2008-1879","article-title":"Chronic fatigue syndrome after infectious mononucleosis in adolescents","volume":"124","author":"Katz","year":"2009","journal-title":"Pediatrics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.canlet.2011.03.003","article-title":"Gammaherpesvirus and lymphoproliferative disorders in immunocompromised patients","volume":"305","author":"Cesarman","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1146\/annurev-pathol-012513-104656","article-title":"Gammaherpesviruses and lymphoproliferative disorders","volume":"9","author":"Cesarman","year":"2014","journal-title":"Annu. Rev. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1002\/rmv.1780","article-title":"Switching of EBV cycles between latent and lytic states","volume":"24","author":"Murata","year":"2014","journal-title":"Rev. Med. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1038\/labinvest.2008.103","article-title":"High levels of Epstein\u2013Barr virus DNA in latently infected gastric adenocarcinoma","volume":"89","author":"Ryan","year":"2009","journal-title":"Lab. Invest."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0065-230X(06)97004-3","article-title":"Lytic cycle switches of oncogenic human gammaherpesviruses","volume":"97","author":"Miller","year":"2007","journal-title":"Adv. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4002","DOI":"10.1182\/blood-2009-07-143545","article-title":"How I treat EBV lymphoproliferation","volume":"114","author":"Heslop","year":"2009","journal-title":"Blood"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13993","DOI":"10.1128\/JVI.79.22.13993-14003.2005","article-title":"Epstein\u2013Barr virus lytic infection contributes to lymphoproliferative disease in a SCID mouse model","volume":"79","author":"Hong","year":"2005","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1128\/JVI.01512-10","article-title":"A new model of Epstein\u2013Barr virus infection reveals an important role for early lytic viral protein expression in the development of lymphomas","volume":"85","author":"Ma","year":"2011","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.clinthera.2018.07.006","article-title":"Antiviral Therapies for Herpesviruses: Current Agents and New Directions","volume":"40","author":"Poole","year":"2018","journal-title":"Clin. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.antiviral.2018.09.016","article-title":"A standardized approach to the evaluation of antivirals against DNA viruses: Polyomaviruses and lymphotropic herpesviruses","volume":"159","author":"Keith","year":"2018","journal-title":"Antiviral Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12422","DOI":"10.1128\/JVI.02231-13","article-title":"Evaluation of novel acyclic nucleoside phosphonates against human and animal gammaherpesviruses revealed an altered metabolism of cyclic prodrugs upon Epstein\u2013Barr virus reactivation in P3HR-1 cells","volume":"87","author":"Coen","year":"2013","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7312","DOI":"10.1128\/AAC.03957-14","article-title":"Spectrum of activity and mechanisms of resistance of various nucleoside derivatives against gammaherpesviruses","volume":"58","author":"Coen","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/jac\/dki240","article-title":"Epstein\u2013Barr virus infections: Prospects for treatment","volume":"56","author":"Gershburg","year":"2005","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2267","DOI":"10.1099\/0022-1317-67-10-2267","article-title":"Acyclovir efficiently inhibits oropharyngeal excretion of Epstein\u2013Barr virus in patients with acute infectious mononucleosis","volume":"67","author":"Ernberg","year":"1986","journal-title":"J. Gen. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/infdis\/174.2.324","article-title":"Acyclovir and prednisolone treatment of acute infectious mononucleosis: A multicenter, double-blind, placebo-controlled study","volume":"174","author":"Tynell","year":"1996","journal-title":"J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.jhep.2006.03.002","article-title":"The paradox of Epstein\u2013Barr virus-associated hepatitis","volume":"44","author":"Negro","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.jhep.2006.02.006","article-title":"The role of Epstein\u2013Barr virus in acute and chronic hepatitis","volume":"44","author":"Drebber","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kimura, H., and Cohen, J.I. (2017). Chronic Active Epstein\u2013Barr Virus Disease. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01867"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41564-018-0334-0","article-title":"Defective Epstein\u2013Barr virus in chronic active infection and haematological malignancy","volume":"4","author":"Okuno","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wass, M., Bauer, M., Pfannes, R., Lorenz, K., Odparlik, A., Muller, L.P., and Wickenhauser, C. (2018). Chronic active Epstein\u2013Barr virus infection of T-cell type, systemic form in an African migrant: Case report and review of the literature on diagnostics standards and therapeutic options. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4861-0"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.canlet.2015.08.007","article-title":"Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment","volume":"369","author":"Petrara","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Dharnidharka, V.R., Webster, A.C., Martinez, O.M., Preiksaitis, J.K., Leblond, V., and Choquet, S. (2016). Post-transplant lymphoproliferative disorders. Nat. Rev. Dis. Primers, 2.","DOI":"10.1038\/nrdp.2015.88"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1056\/NEJMra1702693","article-title":"Post-Transplantation Lymphoproliferative Disorders in Adults","volume":"378","author":"Dierickx","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"729","DOI":"10.5500\/wjt.v6.i4.729","article-title":"Persistent Epstein\u2013Barr viral load in Epstein\u2013Barr viral naive pediatric heart transplant recipients: Risk of late-onset post-transplant lymphoproliferative disease","volume":"6","author":"Das","year":"2016","journal-title":"World J. Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1007\/s00467-017-3627-2","article-title":"Viral load of EBV DNAemia is a predictor of EBV-related post-transplant lymphoproliferative disorders in pediatric renal transplant recipients","volume":"32","author":"Colombini","year":"2017","journal-title":"Pediatr. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1111\/j.1432-2277.2012.01485.x","article-title":"(Val-)Ganciclovir prophylaxis reduces Epstein\u2013Barr virus primary infection in pediatric renal transplantation","volume":"25","author":"Hocker","year":"2012","journal-title":"Transpl. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S1053-2498(01)00407-7","article-title":"Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients","volume":"21","author":"Malouf","year":"2002","journal-title":"J. Heart Lung Transplant."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1002\/lt.21498","article-title":"Efficacy and safety of valganciclovir in liver-transplanted children infected with Epstein\u2013Barr virus","volume":"14","author":"Hierro","year":"2008","journal-title":"Liver Transpl."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/hon.2465","article-title":"Epstein\u2013Barr virus lytic cycle involvement in diffuse large B cell lymphoma","volume":"36","author":"Cohen","year":"2018","journal-title":"Hematol. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1002\/ijc.22839","article-title":"Roles of lytic viral infection and IL-6 in early versus late passage lymphoblastoid cell lines and EBV-associated lymphoproliferative disease","volume":"121","author":"Jones","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13984","DOI":"10.1128\/JVI.79.22.13984-13992.2005","article-title":"Epstein\u2013Barr virus lytic infection is required for efficient production of the angiogenesis factor vascular endothelial growth factor in lymphoblastoid cell lines","volume":"79","author":"Hong","year":"2005","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4045","DOI":"10.4049\/jimmunol.158.9.4045","article-title":"Involvement of IL-10 in the autonomous growth of EBV-transformed B cell lines","volume":"158","author":"Beatty","year":"1997","journal-title":"J. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1128\/AAC.02825-14","article-title":"Antiherpesvirus activities of two novel 4\u2019-thiothymidine derivatives, KAY-2-41 and KAH-39-149, are dependent on viral and cellular thymidine kinases","volume":"58","author":"Coen","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3839","DOI":"10.1128\/JVI.03338-12","article-title":"Activity and mechanism of action of HDVD, a novel pyrimidine nucleoside derivative with high levels of selectivity and potency against gammaherpesviruses","volume":"87","author":"Coen","year":"2013","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/tri.13085","article-title":"Impact of antiviral prophylaxis in adults Epstein\u2013Barr Virus-seronegative kidney recipients on early and late post-transplantation lymphoproliferative disorder onset: A retrospective cohort study","volume":"31","author":"Ville","year":"2018","journal-title":"Transpl. Int."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"\u00d8stensen, A.B., Sanengen, T., Holter, E., Line, P.D., and Almaas, R. (2017). No effect of treatment with intravenous ganciclovir on Epstein\u2013Barr virus viremia demonstrated after pediatric liver transplantation. Pediatr. Transplant., 21.","DOI":"10.1111\/petr.13010"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.jcv.2014.01.005","article-title":"Valganciclovir suppressed Epstein Barr virus reactivation during immunosuppression with alemtuzumab","volume":"59","author":"Gill","year":"2014","journal-title":"J. Clin. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1093\/infdis\/jix263","article-title":"Valganciclovir for the Suppression of Epstein\u2013Barr Virus Replication","volume":"216","author":"Yager","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_40","first-page":"1561","article-title":"Role of cidofovir in the treatment of DNA virus infections, other than CMV infections, in immunocompromised patients","volume":"3","author":"Snoeck","year":"2002","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.antiviral.2014.10.012","article-title":"Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia","volume":"114","author":"Andrei","year":"2015","journal-title":"Antiviral. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1002\/jmv.21165","article-title":"Treatment of locally recurrent Epstein\u2013Barr virus-associated nasopharyngeal carcinoma using the anti-viral agent cidofovir","volume":"80","author":"Yoshizaki","year":"2008","journal-title":"J. Med. Virol."},{"key":"ref_43","first-page":"384","article-title":"The antiviral agent cidofovir [(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine] has pronounced activity against nasopharyngeal carcinoma grown in nude mice","volume":"58","author":"Neyts","year":"1998","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1002\/ijc.21096","article-title":"Ribonucleotide reductase inhibitors enhance cidofovir-induced apoptosis in EBV-positive nasopharyngeal carcinoma xenografts","volume":"116","author":"Wakisaka","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1038\/sj.onc.1206402","article-title":"Antiviral agent cidofovir decreases Epstein\u2013Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies","volume":"22","author":"Abdulkarim","year":"2003","journal-title":"Oncogene"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Afshar, K., Rao, A.P., Patel, V., Forrester, K., and Ganesh, S. (2011). Use of Foscarnet Therapy for EBV Infection following Control of PTLD with Enhancement of Cellular Immunity in a Lung-Transplant Recipient. J. Transplant., 2011.","DOI":"10.1155\/2011\/919651"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1007\/s002770050581","article-title":"Regression of Epstein\u2013Barr virus-associated lymphoproliferative disorders in patients with acquired immunodeficiency syndrome during therapy with foscarnet","volume":"79","author":"Schneider","year":"2000","journal-title":"Ann. Hematol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2365","DOI":"10.1128\/AAC.46.8.2365-2372.2002","article-title":"Potent and selective inhibition of human cytomegalovirus replication by 1263W94, a benzimidazole L-riboside with a unique mode of action","volume":"46","author":"Biron","year":"2002","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7271","DOI":"10.1128\/JVI.73.9.7271-7277.1999","article-title":"Inhibition of Epstein\u2013Barr virus replication by a benzimidazole L-riboside: Novel antiviral mechanism of 5, 6-dichloro-2-(isopropylamino)-1-beta-L-ribofuranosyl-1H-benzimidazole","volume":"73","author":"Zacny","year":"1999","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/rmv.615","article-title":"Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir","volume":"19","author":"Prichard","year":"2009","journal-title":"Rev. Med. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1128\/AAC.01259-10","article-title":"Cytomegalovirus UL97 mutations affecting cyclopropavir and ganciclovir susceptibility","volume":"55","author":"Chou","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1128\/JVI.02426-14","article-title":"Human Cytomegalovirus UL97 Phosphorylates the Viral Nuclear Egress Complex","volume":"89","author":"Sharma","year":"2014","journal-title":"J. Virol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1128\/CMR.00009-10","article-title":"Antiviral drug resistance of human cytomegalovirus","volume":"23","author":"Lurain","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1002\/rmv.574","article-title":"Cytomegalovirus UL97 mutations in the era of ganciclovir and maribavir","volume":"18","author":"Chou","year":"2008","journal-title":"Rev. Med. Virol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1128\/AAC.05559-11","article-title":"Cyclopropavir susceptibility of cytomegalovirus DNA polymerase mutants selected after antiviral drug exposure","volume":"56","author":"Chou","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.1128\/AAC.00511-13","article-title":"Cytomegalovirus UL97 kinase catalytic domain mutations that confer multidrug resistance","volume":"57","author":"Chou","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3021","DOI":"10.1111\/j.1600-6143.2012.04231.x","article-title":"Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: A randomized, double-blind, multicenter controlled trial","volume":"12","author":"Winston","year":"2012","journal-title":"Am. J. Transplant."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S1473-3099(11)70024-X","article-title":"Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: A phase 3, double-blind, placebo-controlled, randomised trial","volume":"11","author":"Marty","year":"2011","journal-title":"Lancet. Infect. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1097\/QCO.0000000000000107","article-title":"Cytomegalovirus","volume":"27","author":"Griffiths","year":"2014","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"12108","DOI":"10.1128\/JVI.01575-09","article-title":"Maribavir inhibits Epstein\u2013Barr virus transcription in addition to viral DNA replication","volume":"83","author":"Wang","year":"2009","journal-title":"J. Virol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.virol.2009.04.007","article-title":"Efficient production of infectious viruses requires enzymatic activity of Epstein\u2013Barr virus protein kinase","volume":"389","author":"Murata","year":"2009","journal-title":"Virology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"5311","DOI":"10.1128\/JVI.03505-12","article-title":"Maribavir inhibits Epstein\u2013Barr virus transcription through the EBV protein kinase","volume":"87","author":"Whitehurst","year":"2013","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4534","DOI":"10.1128\/JVI.02487-09","article-title":"The Epstein\u2013Barr virus (EBV)-encoded protein kinase, EBV-PK, but not the thymidine kinase (EBV-TK), is required for ganciclovir and acyclovir inhibition of lytic viral production","volume":"84","author":"Meng","year":"2010","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1177\/095632020001100302","article-title":"Synthesis and enantioselectivity of the antiviral effects of (R,Z)-,(S,Z)-methylenecyclopropane analogues of purine nucleosides and phosphoralaninate prodrugs: Influence of heterocyclic base, type of virus and host cells","volume":"11","author":"Qiu","year":"2000","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1021\/jm030316s","article-title":"Synthesis and antiviral activity of (Z)- and (E)-2,2-[bis(hydroxymethyl)cyclopropylidene]methylpurines and -pyrimidines: Second-generation methylenecyclopropane analogues of nucleosides","volume":"47","author":"Zhou","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.1128\/AAC.00429-13","article-title":"Synthesis and antiviral activities of methylenecyclopropane analogs with 6-alkoxy and 6-alkylthio substitutions that exhibit broad-spectrum antiviral activity against human herpesviruses","volume":"57","author":"Prichard","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1021\/jm0205245","article-title":"Structure-activity relationships of (S,Z)-2-aminopurine methylenecyclopropane analogues of nucleosides. Variation of purine-6 substituents and activity against herpesviruses and hepatitis B virus","volume":"46","author":"Chen","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1128\/AAC.49.3.1039-1045.2005","article-title":"In vitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpesvirus replication","volume":"49","author":"Kern","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1016\/j.bmc.2012.02.031","article-title":"Synthesis and antiviral activity of 6-deoxycyclopropavir, a new prodrug of cyclopropavir","volume":"20","author":"Li","year":"2012","journal-title":"Bioorg. Med. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4682","DOI":"10.1128\/AAC.00571-11","article-title":"Cyclopropavir inhibits the normal function of the human cytomegalovirus UL97 kinase","volume":"55","author":"James","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1128\/AAC.50.4.1336-1341.2006","article-title":"Activity and mechanism of action of N-methanocarbathymidine against herpesvirus and orthopoxvirus infections","volume":"50","author":"Prichard","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3851\/IMP1901","article-title":"Efficacy of orally administered low dose N-methanocarbathymidine against lethal herpes simplex virus type-2 infections of mice","volume":"22","author":"Quenelle","year":"2011","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/2040206614566581","article-title":"Efficacy of N-methanocarbathymidine against genital herpes simplex virus type 2 shedding and infection in guinea pigs","volume":"24","author":"Bernstein","year":"2015","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"A84","DOI":"10.1016\/j.antiviral.2009.01.005","article-title":"Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: Current state of the art","volume":"82","author":"Hostetler","year":"2009","journal-title":"Antiviral. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.bbmt.2018.09.038","article-title":"A Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Oral Brincidofovir for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Cell Transplantation","volume":"25","author":"Marty","year":"2019","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Wilson, J.B., Manet, E., Gruffat, H., Busson, P., Blondel, M., and Fahraeus, R. (2018). EBNA1: Oncogenic Activity, Immune Evasion and Biochemical Functions Provide Targets for Novel Therapeutic Strategies against Epstein\u2013Barr Virus- Associated Cancers. Cancers, 10.","DOI":"10.3390\/cancers10040109"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5307","DOI":"10.7150\/thno.26823","article-title":"EBNA1-targeted inhibitors: Novel approaches for the treatment of Epstein\u2013Barr virus-associated cancers","volume":"8","author":"Jiang","year":"2018","journal-title":"Theranostics"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.antiviral.2014.01.018","article-title":"Small molecule inhibition of Epstein\u2013Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome","volume":"104","author":"Lee","year":"2014","journal-title":"Antiviral. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s10822-016-9899-y","article-title":"Computational analysis of EBNA1 \u201cdruggability\u201d suggests novel insights for Epstein\u2013Barr virus inhibitor design","volume":"30","author":"Gianti","year":"2016","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1099\/0022-1317-74-10-2263","article-title":"Topoisomerase I and II activities are required for Epstein\u2013Barr virus replication","volume":"74","author":"Kawanishi","year":"1993","journal-title":"J. Gen. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"8090","DOI":"10.1128\/JVI.02379-08","article-title":"Topoisomerase I and RecQL1 function in Epstein\u2013Barr virus lytic reactivation","volume":"83","author":"Wang","year":"2009","journal-title":"J. Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.antiviral.2014.05.003","article-title":"Antiviral activity of topoisomerase II catalytic inhibitors against Epstein\u2013Barr virus","volume":"107","author":"Wu","year":"2014","journal-title":"Antiviral. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1128\/AAC.05274-11","article-title":"Potent antiviral activity of topoisomerase I and II inhibitors against Kaposi\u2019s sarcoma-associated herpesvirus","volume":"56","author":"Wang","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Widman, D.G., Gornisiewicz, S., Shacham, S., and Tamir, S. (2018). In vitro toxicity and efficacy of verdinexor, an exportin 1 inhibitor, on opportunistic viruses affecting immunocompromised individuals. PLoS ONE, 13.","DOI":"10.1101\/351825"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.tim.2013.03.005","article-title":"Potential of protein kinase inhibitors for treating herpesvirus-associated disease","volume":"21","author":"Li","year":"2013","journal-title":"Trends Microbiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1399-3062.2009.00448.x","article-title":"Lower incidence of cytomegalovirus infection with everolimus versus mycophenolate mofetil in de novo cardiac transplant recipients: A randomized, multicenter study","volume":"12","author":"Vigano","year":"2010","journal-title":"Transpl. Infect. Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1097\/01.tp.0000290686.68910.bd","article-title":"A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus","volume":"84","author":"Hill","year":"2007","journal-title":"Transplantation"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1111\/tid.12007","article-title":"Everolimus is associated with a reduced incidence of cytomegalovirus infection following de novo cardiac transplantation","volume":"15","author":"Kobashigawa","year":"2013","journal-title":"Transpl. Infect. Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.antiviral.2018.12.004","article-title":"Everolimus delayed and suppressed cytomegalovirus DNA synthesis, spread of the infection, and alleviated cytomegalovirus infection","volume":"162","author":"Tan","year":"2019","journal-title":"Antiviral. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.1248\/bpb.31.2018","article-title":"Inhibition of the Epstein\u2013Barr virus lytic cycle by andrographolide","volume":"31","author":"Lin","year":"2008","journal-title":"Biol. Pharm. Bull."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.ejmech.2012.07.030","article-title":"Anti-HIV activity of semisynthetic derivatives of andrographolide and computational study of HIV-1 gp120 protein binding","volume":"56","author":"Uttekar","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1055\/s-0030-1250659","article-title":"Stage of action of naturally occurring andrographolides and their semisynthetic analogues against herpes simplex virus type 1 in vitro","volume":"77","author":"Aromdee","year":"2011","journal-title":"Planta Med."},{"key":"ref_93","first-page":"298","article-title":"Biological activities and corresponding SARs of andrographolide and its derivatives","volume":"13","author":"Zhou","year":"2013","journal-title":"Mini. Rev. Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1002\/ptr.1765","article-title":"Antiviral properties of ent-labdene diterpenes of Andrographis paniculata nees, inhibitors of herpes simplex virus type 1","volume":"19","author":"Wiart","year":"2005","journal-title":"Phytother. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.3390\/molecules19011258","article-title":"Inhibition of Epstein\u2013Barr virus lytic cycle by an ethyl acetate subfraction separated from Polygonum cuspidatum root and its major component, emodin","volume":"19","author":"Yiu","year":"2014","journal-title":"Molecules"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ejphar.2013.02.021","article-title":"Emodin ameliorates lipopolysaccharide-induced mastitis in mice by inhibiting activation of NF-kappaB and MAPKs signal pathways","volume":"705","author":"Li","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2480","DOI":"10.1016\/j.lfs.2006.08.008","article-title":"Emodin inhibits TNF alpha-induced MMP-1 expression through suppression of activator protein-1 (AP-1)","volume":"79","author":"Lee","year":"2006","journal-title":"Life Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/ptr.2138","article-title":"Aloe-emodin suppressed NMDA-induced apoptosis of retinal ganglion cells through regulation of ERK phosphorylation","volume":"21","author":"Lin","year":"2007","journal-title":"Phytother. Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1093\/carcin\/bgs364","article-title":"(\u2212)-Epigallocatechin-3-gallate inhibition of Epstein\u2013Barr virus spontaneous lytic infection involves ERK1\/2 and PI3-K\/Akt signaling in EBV-positive cells","volume":"34","author":"Liu","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/S0006-291X(03)00067-6","article-title":"Inhibition of Epstein\u2013Barr virus lytic cycle by (\u2212)-epigallocatechin gallate","volume":"301","author":"Chang","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1021\/np400757k","article-title":"Potential antiviral lignans from the roots of Saururus chinensis with activity against Epstein\u2013Barr virus lytic replication","volume":"77","author":"Cui","year":"2014","journal-title":"J. Nat. Prod."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/S0031-9422(03)00391-1","article-title":"Lignans from Saururus chinensis inhibiting the transcription factor NF-kappaB","volume":"64","author":"Hwang","year":"2003","journal-title":"Phytochemistry"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.antiviral.2009.11.002","article-title":"Lignan, sesquilignans and dilignans, novel HIV-1 protease and cytopathic effect inhibitors purified from the rhizomes of Saururus chinensis","volume":"85","author":"Lee","year":"2010","journal-title":"Antiviral. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1055\/s-2008-1034310","article-title":"Cardiovascular effects of lignans isolated from Saururus chinensis","volume":"74","author":"Oh","year":"2008","journal-title":"Planta Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"5462","DOI":"10.1021\/jm0601912","article-title":"Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents","volume":"49","author":"Yu","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.antiviral.2009.12.002","article-title":"Inhibition of the Epstein\u2013Barr virus lytic cycle by moronic acid","volume":"85","author":"Chang","year":"2010","journal-title":"Antiviral. Res."},{"key":"ref_107","first-page":"72","article-title":"Anti-herpes simplex virus activity of moronic acid purified from Rhus javanica in vitro and in vivo","volume":"289","author":"Kurokawa","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1099\/vir.0.031609-0","article-title":"Inhibition of the Epstein\u2013Barr virus lytic cycle by protoapigenone","volume":"92","author":"Tung","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.antiviral.2013.07.009","article-title":"Antiviral activity of angelicin against gammaherpesviruses","volume":"100","author":"Cho","year":"2013","journal-title":"Antiviral. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1021\/jm901570x","article-title":"Anti-influenza drug discovery: Structure-activity relationship and mechanistic insight into novel angelicin derivatives","volume":"53","author":"Yeh","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/1011-1344(94)07046-6","article-title":"Antiretroviral activity of furocoumarins plus UVA light detected by a replication-defective retrovirus","volume":"26","author":"Miolo","year":"1994","journal-title":"J. Photochem. Photobiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"8028","DOI":"10.1128\/JVI.00722-14","article-title":"Activation and repression of Epstein\u2013Barr Virus and Kaposi\u2019s sarcoma-associated herpesvirus lytic cycles by short- and medium-chain fatty acids","volume":"88","author":"Gorres","year":"2014","journal-title":"J. Virol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1002\/ijc.27439","article-title":"Activation of lytic cycle of Epstein\u2013Barr virus by suberoylanilide hydroxamic acid leads to apoptosis and tumor growth suppression of nasopharyngeal carcinoma","volume":"131","author":"Hui","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1158\/1078-0432.CCR-09-2424","article-title":"Viral response to chemotherapy in endemic burkitt lymphoma","volume":"16","author":"Tang","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/nm.1864","article-title":"Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors","volume":"14","author":"Fu","year":"2008","journal-title":"Nat. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4706","DOI":"10.1128\/JVI.00116-08","article-title":"Histone hyperacetylation occurs on promoters of lytic cycle regulatory genes in Epstein\u2013Barr virus-infected cell lines which are refractory to disruption of latency by histone deacetylase inhibitors","volume":"82","author":"Countryman","year":"2008","journal-title":"J. Virol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Van Diemen, F.R., Kruse, E.M., Hooykaas, M.J., Bruggeling, C.E., Schurch, A.C., van Ham, P.M., Imhof, S.M., Nijhuis, M., Wiertz, E.J., and Lebbink, R.J. (2016). CRISPR\/Cas9-Mediated Genome Editing of Herpesviruses Limits Productive and Latent Infections. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005701"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/5\/997\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:38:17Z","timestamp":1760186297000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/5\/997"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,12]]},"references-count":117,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["molecules24050997"],"URL":"https:\/\/doi.org\/10.3390\/molecules24050997","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,12]]}}}