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AZ-9B783"]}],"id":[{"id":"10.13039\/100008672","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Volkswagen-Stiftung","award":["401821119\/GRK2504\/A1-M.M."],"award-info":[{"award-number":["401821119\/GRK2504\/A1-M.M."]}]},{"name":"Volkswagen-Stiftung","award":["DeeP-CMV\/AP-5\/MM"],"award-info":[{"award-number":["DeeP-CMV\/AP-5\/MM"]}]},{"name":"Volkswagen-Stiftung","award":["M.M.\/H.S. AZ-2022.073.1"],"award-info":[{"award-number":["M.M.\/H.S. AZ-2022.073.1"]}]},{"name":"Volkswagen-Stiftung","award":["M.M.\/S.B.T. AZ-9B783"],"award-info":[{"award-number":["M.M.\/S.B.T. AZ-9B783"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Despite the availability of currently approved antiviral drugs, infections with human cytomegalovirus (HCMV) still cause clinically challenging, sometimes life-threatening situations. There is an urgent need for enhanced anti-HCMV drugs that offer improved efficacy, reduced dosages and options for long-term treatment without risk of the development of viral drug resistance. Recently, we reported the pronounced anti-HCMV efficacy of pharmacological inhibitors of cyclin-dependent kinases (CDKs), in particular, the potential of utilizing drug synergies upon combination treatment with inhibitors of host CDKs and the viral CDK-like kinase pUL97 (vCDK\/pUL97). Here, we expand this finding by further assessing the in vitro synergistic antiviral interaction between vCDK and CDK inhibitors towards HCMV as well as non-human cytomegaloviruses. An extension of this synergy approach was achieved in vivo by using the recombinant MCMV-UL97\/mouse model, confirming the high potential of combination treatment with the clinically approved vCDK inhibitor maribavir (MBV) and the developmental CDK7 inhibitor LDC4297. Moreover, mechanistic aspects of this synergistic drug combination were illustrated on the levels of intracellular viral protein transport and viral genome replication. The analysis of viral drug resistance did not reveal resistance formation in the case of MBV + LDC4297 combination treatment. Spanning various investigational levels, these new results strongly support our concept, employing the great potential of anti-HCMV synergistic drug treatment.<\/jats:p>","DOI":"10.3390\/pharmaceutics15122680","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T03:33:56Z","timestamp":1701056036000},"page":"2680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers"],"prefix":"10.3390","volume":"15","author":[{"given":"Markus","family":"Wild","sequence":"first","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), Schlossgarten 4, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8122-6113","authenticated-orcid":false,"given":"Dubravka","family":"Karner","sequence":"additional","affiliation":[{"name":"Center for Proteomics, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5537-438X","authenticated-orcid":false,"given":"Jan","family":"Eickhoff","sequence":"additional","affiliation":[{"name":"Lead Discovery Center GmbH, Otto-Hahn-Str. 15, 44227 Dortmund, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Wagner","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), Schlossgarten 4, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintawee","family":"Kicuntod","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), Schlossgarten 4, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, California National Primate Research Center, University of California, 3146 Tupper Hall, 1 Shields Avenue, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Barry","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, California National Primate Research Center, University of California, 3146 Tupper Hall, 1 Shields Avenue, Davis, CA 95616, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stipan","family":"Jonji\u0107","sequence":"additional","affiliation":[{"name":"Center for Proteomics, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3299-1334","authenticated-orcid":false,"given":"Tihana","family":"Lenac Rovi\u0161","sequence":"additional","affiliation":[{"name":"Center for Proteomics, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, 51000 Rijeka, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Marschall","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), Schlossgarten 4, 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/rmv.655","article-title":"Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection","volume":"20","author":"Cannon","year":"2010","journal-title":"Rev. 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