{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:13:58Z","timestamp":1790255638066,"version":"4.1.0"},"reference-count":66,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,27]],"date-time":"2021-11-27T00:00:00Z","timestamp":1637971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bayerische Forschungsstiftung","award":["grant DeeP-CMV\/AP-5\/MM"],"award-info":[{"award-number":["grant DeeP-CMV\/AP-5\/MM"]}]},{"name":"Bayerische Forschungsstiftung","award":["IMU-COVID\/MM"],"award-info":[{"award-number":["IMU-COVID\/MM"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["Research Training Group GRK2504 (DFG, subproject A1)"],"award-info":[{"award-number":["Research Training Group GRK2504 (DFG, subproject A1)"]}]},{"name":"Wilhelm Sander-Stiftung","award":["WSS MA\/SBT 2018.121.1"],"award-info":[{"award-number":["WSS MA\/SBT 2018.121.1"]}]},{"name":"DAAD-Go8","award":["grants 2017-18\/MM-WDR-STH-JM"],"award-info":[{"award-number":["grants 2017-18\/MM-WDR-STH-JM"]}]},{"name":"DAAD-Go8","award":["2020-21\/MM-WDR"],"award-info":[{"award-number":["2020-21\/MM-WDR"]}]},{"name":"Australian National Health and Medical Research Council","award":["grant APP1127717-Hamilton"],"award-info":[{"award-number":["grant APP1127717-Hamilton"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 \u00b5M and CC50 of 0.175 \u00b5M (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.<\/jats:p>","DOI":"10.3390\/ijms222312858","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T23:22:28Z","timestamp":1638314548000},"page":"12858","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Development of a PROTAC-Based Targeting Strategy Provides a Mechanistically Unique Mode of Anti-Cytomegalovirus Activity"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3011-8416","authenticated-orcid":false,"given":"Friedrich","family":"Hahn","sequence":"first","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart T.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Serology and Virology Division, NSW Health Pathology Microbiology, Prince of Wales Hospital, Schools of Women\u2019s and Children\u2019s Health, Medicine and Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Wangen","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Wild","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 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), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Br\u00fcckner","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, Friedrich-Alexander University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmine E. L.","family":"Follett","sequence":"additional","affiliation":[{"name":"Serology and Virology Division, NSW Health Pathology Microbiology, Prince of Wales Hospital, Schools of Women\u2019s and Children\u2019s Health, Medicine and Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry I, FAU, 91058 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Kheimar","sequence":"additional","affiliation":[{"name":"Institute of Virology, Freie Universit\u00e4t Berlin, 14163 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1328-2695","authenticated-orcid":false,"given":"Benedikt B.","family":"Kaufer","sequence":"additional","affiliation":[{"name":"Institute of Virology, Freie Universit\u00e4t Berlin, 14163 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0988-7827","authenticated-orcid":false,"given":"William D.","family":"Rawlinson","sequence":"additional","affiliation":[{"name":"Serology and Virology Division, NSW Health Pathology Microbiology, Prince of Wales Hospital, Schools of Women\u2019s and Children\u2019s Health, Medicine and Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2031, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-0951","authenticated-orcid":false,"given":"Svetlana B.","family":"Tsogoeva","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry I, FAU, 91058 Erlangen, Germany"}],"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), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1002\/path.4437","article-title":"The pathogenesis of human cytomegalovirus","volume":"235","author":"Griffiths","year":"2015","journal-title":"J. Pathol."},{"key":"ref_2","first-page":"75","article-title":"Coinfection with herpesviruses in young children of HIV-infected women","volume":"6","author":"Sever","year":"1995","journal-title":"Pediatr. AIDS HIV Infect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1080\/17512433.2018.1501557","article-title":"Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation","volume":"11","author":"Meesing","year":"2018","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"197829","DOI":"10.1016\/j.virusres.2019.197829","article-title":"Persistent HCMV infection of a glioblastoma cell line contributes to the development of resistance to temozolomide","volume":"276","author":"Singh","year":"2020","journal-title":"Virus Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1128\/CMR.15.4.680-715.2002","article-title":"Diagnosis and management of human cytomegalovirus infection in the mother, fetus, and newborn infant","volume":"15","author":"Revello","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"731","DOI":"10.2217\/fmb.09.40","article-title":"Molecular targets for antiviral therapy of cytomegalovirus infections","volume":"4","author":"Marschall","year":"2009","journal-title":"Future Microbiol."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1056\/NEJMoa1706640","article-title":"Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation","volume":"377","author":"Marty","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1080\/14656566.2019.1637418","article-title":"An overview of letermovir: A cytomegalovirus prophylactic option","volume":"20","author":"Gerna","year":"2019","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1128\/AAC.05908-11","article-title":"In vitro evaluation of the activities of the novel anticytomegalovirus compound AIC246 (letermovir) against herpesviruses and other human pathogenic viruses","volume":"56","author":"Marschall","year":"2012","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.antiviral.2018.09.003","article-title":"New therapies for human cytomegalovirus infections","volume":"159","author":"Britt","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1093\/bmb\/ldz031","article-title":"Advances in the treatment of cytomegalovirus","volume":"131","author":"Krishna","year":"2019","journal-title":"Br. Med. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Steingruber, M., and Marschall, M. (2020). The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting. Microorganisms, 8.","DOI":"10.3390\/microorganisms8040515"},{"key":"ref_14","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_15","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_16","doi-asserted-by":"crossref","first-page":"5663","DOI":"10.1128\/JVI.73.7.5663-5670.1999","article-title":"A recombinant human cytomegalovirus with a large deletion in UL97 has a severe replication deficiency","volume":"73","author":"Prichard","year":"1999","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hamirally, S., Kamil, J.P., Ndassa-Colday, Y.M., Lin, A.J., Jahng, W.J., Baek, M.-C., Noton, S., Silva, L.A., Simpson-Holley, M., and Knipe, D.M. (2009). Viral mimicry of Cdc2\/cyclin-dependent kinase 1 mediates disruption of nuclear lamina during human cytomegalovirus nuclear egress. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000275"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1128\/JVI.77.2.905-914.2003","article-title":"The human cytomegalovirus UL97 protein kinase, an antiviral drug target, is required at the stage of nuclear egress","volume":"77","author":"Krosky","year":"2003","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"33357","DOI":"10.1074\/jbc.M502672200","article-title":"Cellular p32 recruits cytomegalovirus kinase pUL97 to redistribute the nuclear lamina","volume":"280","author":"Marschall","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1099\/vir.0.005231-0","article-title":"Cytomegaloviral proteins that associate with the nuclear lamina: Components of a postulated nuclear egress complex","volume":"90","author":"Milbradt","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1073\/pnas.98.4.1895","article-title":"Distinct and separate roles for herpesvirus-conserved UL97 kinase in cytomegalovirus DNA synthesis and encapsidation","volume":"98","author":"Wolf","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.antiviral.2018.11.008","article-title":"In vivo proof-of-concept for two experimental antiviral drugs, both directed to cellular targets, using a murine cytomegalovirus model","volume":"161","author":"Sonntag","year":"2019","journal-title":"Antivir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1099\/jgv.0.000931","article-title":"Protein kinases responsible for the phosphorylation of the nuclear egress core complex of human cytomegalovirus","volume":"98","author":"Sonntag","year":"2017","journal-title":"J. Gen. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.antiviral.2016.08.005","article-title":"The chemical class of quinazoline compounds provides a core structure for the design of anticytomegaloviral kinase inhibitors","volume":"134","author":"Hutterer","year":"2016","journal-title":"Antivir. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1099\/jgv.0.000337","article-title":"New insight into the phosphorylation-regulated intranuclear localization of human cytomegalovirus pUL69 mediated by cyclin-dependent kinases (CDKs) and viral CDK orthologue pUL97","volume":"97","author":"Graf","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2062","DOI":"10.1128\/AAC.04534-14","article-title":"A novel CDK7 inhibitor of the Pyrazolotriazine class exerts broad-spectrum antiviral activity at nanomolar concentrations","volume":"59","author":"Hutterer","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.antiviral.2013.04.017","article-title":"Profiling of the kinome of cytomegalovirus-infected cells reveals the functional importance of host kinases Aurora A, ABL and AMPK","volume":"99","author":"Hutterer","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1099\/vir.0.030494-0","article-title":"Recruitment of cyclin-dependent kinase 9 to nuclear compartments during cytomegalovirus late replication: Importance of an interaction between viral pUL69 and cyclin T1","volume":"92","author":"Feichtinger","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8605","DOI":"10.1074\/jbc.M805693200","article-title":"Cyclin-dependent Kinases Phosphorylate the Cytomegalovirus RNA Export Protein pUL69 and Modulate Its Nuclear Localization and Activity","volume":"284","author":"Rechter","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.antiviral.2018.07.013","article-title":"Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus","volume":"157","author":"Chou","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wild, M., Kicuntod, J., Seyler, L., Wangen, C., Bertzbach, L.D., Conradie, A.M., Kaufer, B.B., Wagner, S., Michel, D., and Eickhoff, J. (2021). Combinatorial Drug Treatments Reveal Promising Anticytomegaloviral Profiles for Clinically Relevant Pharmaceutical Kinase Inhibitors (PKIs). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020575"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hertel, L., Chou, S., and Mocarski, E.S. (2007). Viral and cell cycle-regulated kinases in cytomegalovirus-induced pseudomitosis and replication. PLoS Pathog., 3.","DOI":"10.1371\/journal.ppat.0030006"},{"key":"ref_33","unstructured":"Chou, T.C., and Martin, N. (2005). CompuSyn for Drug Combinations: PC Soft-ware and User\u2019s Guide: A Computer Program for Quantitation of Synergism and Antagonism in Drug Combinations, and the Determination of IC50 and ED50 and LD50 Values, ComboSyn Inc.. Available online: http:\/\/www.combosyn.com\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzym. Regul."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"33779","DOI":"10.18632\/oncotarget.16810","article-title":"SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains","volume":"8","author":"Rzymski","year":"2017","journal-title":"Oncotarget"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ebiom.2018.12.022","article-title":"Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma","volume":"39","author":"Ma","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_37","first-page":"1929","article-title":"Targeting CDK9: A novel biomarker in the treatment of endometrial cancer","volume":"44","author":"He","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Cheng, S., Yang, G.-J., Wang, W., Ma, D.-L., and Leung, C.-H. (2021). Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein\u2013protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells. Genes Dis.","DOI":"10.1016\/j.gendis.2021.06.005"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1182\/blood-2018-05-852798","article-title":"Crbn (I391V) is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice","volume":"132","author":"Fink","year":"2018","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/nature14610","article-title":"Lenalidomide induces ubiquitination and degradation of CK1alpha in del(5q) MDS","volume":"523","author":"Kronke","year":"2015","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hahn, F., H\u00e4ge, S., Herrmann, A., Wangen, C., Kicuntod, J., Jungnickl, D., Tillmanns, J., M\u00fcller, R., Fraedrich, K., and \u00dcberla, K. (2021). Methodological Development of a Multi-Readout Assay for the Assessment of Antiviral Drugs against SARS-CoV-2. Pathogens, 10.","DOI":"10.3390\/pathogens10091076"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"113814","DOI":"10.1016\/j.ejmech.2021.113814","article-title":"Indomethacin-based PROTACs as pan-coronavirus antiviral agents","volume":"226","author":"Desantis","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1038\/nm.4184","article-title":"Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen","volume":"22","author":"Xu","year":"2016","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3479","DOI":"10.1172\/JCI73805","article-title":"CDK9 inhibitor FIT-039 prevents replication of multiple DNA viruses","volume":"124","author":"Yamamoto","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7124","DOI":"10.1073\/pnas.1521738113","article-title":"PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer","volume":"113","author":"Raina","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1016\/j.chembiol.2015.05.009","article-title":"Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4","volume":"22","author":"Lu","year":"2015","journal-title":"Chem. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1126\/science.aab1433","article-title":"DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation","volume":"348","author":"Winter","year":"2015","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3564","DOI":"10.1021\/acs.biochem.8b00391","article-title":"Targeting the C481S Ibrutinib-Resistance Mutation in Bruton\u2019s Tyrosine Kinase Using PROTAC-Mediated Degradation","volume":"57","author":"Buhimschi","year":"2018","journal-title":"Biochemistry"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s42003-018-0105-8","article-title":"Androgen receptor degradation by the proteolysis-targeting chimera ARCC-4 outperforms enzalutamide in cellular models of prostate cancer drug resistance","volume":"1","author":"Salami","year":"2018","journal-title":"Commun. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/anie.201507634","article-title":"Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL","volume":"55","author":"Lai","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/s41422-018-0055-1","article-title":"PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies","volume":"28","author":"Sun","year":"2018","journal-title":"Cell Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1038\/s41375-019-0440-x","article-title":"Degradation of Bruton\u2019s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas","volume":"33","author":"Sun","year":"2019","journal-title":"Leukemia"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/s41589-019-0294-6","article-title":"BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design","volume":"15","author":"Farnaby","year":"2019","journal-title":"Nat. Chem. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.chembiol.2017.09.010","article-title":"Lessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead","volume":"25","author":"Bondeson","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.1038\/s41467-019-11429-w","article-title":"Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations","volume":"10","author":"Du","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1128\/AAC.44.6.1588-1597.2000","article-title":"Recombinant green fluorescent protein-expressing human cytomegalovirus as a tool for screening antiviral agents","volume":"44","author":"Marschall","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e01627-20","DOI":"10.1128\/AAC.01627-20","article-title":"Investigational Antiviral Therapy Models for the Prevention and Treatment of Congenital Cytomegalovirus Infection during Pregnancy","volume":"65","author":"Hamilton","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Goodwin, T.J., McCarthy, M., Osterrieder, N., Cohrs, R.J., and Kaufer, B.B. (2013). Three-dimensional normal human neural progenitor tissue-like assemblies: A model of persistent varicella-zoster virus infection. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003512"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.antiviral.2017.04.003","article-title":"Inhibitors of dual-specificity tyrosine phosphorylation-regulated kinases (DYRK) exert a strong anti-herpesviral activity","volume":"143","author":"Hutterer","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1099\/jgv.0.001370","article-title":"Differential upregulation of host cell protein kinases by the replication of alpha-, beta- and gamma-herpesviruses provides a signature of virus-specific signalling","volume":"101","author":"Marschall","year":"2020","journal-title":"J. Gen. Virol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Herrmann, A., Jungnickl, D., Cordsmeier, A., Peter, A.S., \u00dcberla, K., and Ensser, A. (2021). Cloning of a Passage-Free SARS-CoV-2 Genome and Mutagenesis Using Red Recombination. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910188"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1128\/JVI.02588-15","article-title":"Human Cytomegalovirus Modulates Expression of Noncanonical Wnt Receptor ROR2 To Alter Trophoblast Migration","volume":"90","author":"Ford","year":"2016","journal-title":"J. Virol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.placenta.2018.10.002","article-title":"Human cytomegalovirus utilises cellular dual-specificity tyrosine phosphorylation-regulated kinases during placental replication","volume":"72\u201373","author":"Hamilton","year":"2018","journal-title":"Placenta"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/nprot.2008.75","article-title":"Neutral red uptake assay for the estimation of cell viability\/cytotoxicity","volume":"3","author":"Repetto","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.antiviral.2018.09.012","article-title":"Novel cytomegalovirus-inhibitory compounds of the class pyrrolopyridines show a complex pattern of target binding that suggests an unusual mechanism of antiviral activity","volume":"159","author":"Hahn","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"104861","DOI":"10.1016\/j.antiviral.2020.104861","article-title":"Target verification of artesunate-related antiviral drugs: Assessing the role of mitochondrial and regulatory proteins by click chemistry and fluorescence labeling","volume":"180","author":"Hahn","year":"2020","journal-title":"Antivir. 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