{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T02:58:53Z","timestamp":1771901933558,"version":"3.50.1"},"reference-count":30,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["EI 423\/4-1, MA 1289\/8-1, MU 1477\/10-1"],"award-info":[{"award-number":["EI 423\/4-1, MA 1289\/8-1, MU 1477\/10-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Nuclear egress is an essential process in the replication of human cytomegalovirus (HCMV), as it enables the migration of newly formed viral capsids from the nucleus into the cytoplasm. Inhibition of the HCMV core nuclear egress complex (core NEC), composed of viral proteins pUL50 and pUL53, has been proposed as a potential new target for the treatment of HCMV infection and disease. Here, we present a new type of small molecule inhibitors of HCMV core NEC formation, which inhibit the pUL50-pUL53 interaction at nanomolar concentrations. These inhibitors, i.e., verteporfin and merbromin, were identified through the screening of the Prestwick Chemical Library\u00ae of approved drug compounds. The inhibitory effect of merbromin is both compound- and target-specific, as no inhibition was seen for other mercury-organic compounds. Furthermore, merbromin does not inhibit an unrelated protein\u2013protein interaction either. More importantly, merbromin was found to inhibit HCMV infection of cells in three different assays, as well as to disrupt HCMV NEC nuclear rim formation. Thus, while not being an ideal drug candidate by itself, merbromin may serve as a blueprint for small molecules with high HCMV core NEC inhibitory potential, as candidates for novel anti-herpesviral drugs.<\/jats:p>","DOI":"10.3390\/v13030471","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T02:51:48Z","timestamp":1615776708000},"page":"471","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors"],"prefix":"10.3390","volume":"13","author":[{"given":"Sewar","family":"Alkhashrom","sequence":"first","affiliation":[{"name":"Division of Medicinal Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-N\u00fcrnberg (FAU), 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jintawee","family":"Kicuntod","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sigrun","family":"H\u00e4ge","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Schweininger","sequence":"additional","affiliation":[{"name":"Division of Biotechnology, Department of Biology, University of Erlangen-N\u00fcrnberg (FAU), 91052 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yves A.","family":"Muller","sequence":"additional","affiliation":[{"name":"Division of Biotechnology, Department of Biology, University of Erlangen-N\u00fcrnberg (FAU), 91052 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Lischka","sequence":"additional","affiliation":[{"name":"AiCuris Anti-Infective Cures GmbH, 42117 Wuppertal, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manfred","family":"Marschall","sequence":"additional","affiliation":[{"name":"Institute for Clinical and Molecular Virology, University of Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6683-9456","authenticated-orcid":false,"given":"Jutta","family":"Eichler","sequence":"additional","affiliation":[{"name":"Division of Medicinal Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-N\u00fcrnberg (FAU), 91058 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"201","DOI":"10.2174\/187152609787847758","article-title":"Drug targets in cytomegalovirus infection","volume":"9","author":"Andrei","year":"2009","journal-title":"Infect. Disord. Drug Targets"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/pin.12502","article-title":"Pathogenesis of developmental anomalies of the central nervous system induced by congenital cytomegalovirus infection","volume":"67","author":"Kawasaki","year":"2017","journal-title":"Pathol. Int."},{"key":"ref_3","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_4","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_5","doi-asserted-by":"crossref","unstructured":"Mercorelli, B., Luganini, A., Celegato, M., Pal\u00f9, G., Gribaudo, G., Lepesheva, G.I., and Loregian, A. (2020). The Clinically Approved Antifungal Drug Posaconazole Inhibits Human Cytomegalovirus Replication. Antimicrob. Agents Chemother.","DOI":"10.1128\/AAC.00056-20"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3896","DOI":"10.1021\/acs.jmedchem.9b01501","article-title":"Validation and Characterization of Five Distinct Novel Inhibitors of Human Cytomegalovirus","volume":"63","author":"Kapoor","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Marschall, M., Muller, Y.A., Diewald, B., Sticht, H., and Milbradt, J. (2017). The human cytomegalovirus nuclear egress complex unites multiple functions: Recruitment of effectors, nuclear envelope rearrangement, and docking to nuclear capsids. Rev. Med. Virol., 27.","DOI":"10.1002\/rmv.1934"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1099\/jgv.0.000495","article-title":"Cytomegalovirus pUL50 is the multi-interacting determinant of the core nuclear egress complex (NEC) that recruits cellular accessory NEC components","volume":"97","author":"Sonntag","year":"2016","journal-title":"J. Gen. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1074\/mcp.M113.035782","article-title":"Proteomic analysis of the multimeric nuclear egress complex of human cytomegalovirus","volume":"13","author":"Milbradt","year":"2014","journal-title":"Mol. Cell Prot."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"27452","DOI":"10.1074\/jbc.C115.686527","article-title":"Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions","volume":"290","author":"Walzer","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kicuntod, J., Alkhashrom, S., H\u00e4ge, S., Diewald, B., M\u00fcller, R., Hahn, F., Lischka, P., Sticht, H., Eichler, J., and Marschall, M. (2021). Properties of oligomeric interaction of the cytomegalovirus core nuclear egress complex (NEC) and its sensitivity to an NEC inhibitory small molecule. Viruses, 13.","DOI":"10.3390\/v13030462"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1074\/jbc.RA119.011546","article-title":"High-resolution crystal structures of two prototypical beta- and gamma-herpesviral nuclear egress complexes unravel the determinants of subfamily specificity","volume":"295","author":"Muller","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Marschall, M., Hage, S., Conrad, M., Alkhashrom, S., Kicuntod, J., Schweininger, J., Kriegel, M., Losing, J., Tillmanns, J., and Neipel, F. (2020). Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties. Viruses, 12.","DOI":"10.3390\/v12060683"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2937","DOI":"10.15252\/embj.201592651","article-title":"Unexpected features and mechanism of heterodimer formation of a herpesvirus nuclear egress complex","volume":"34","author":"Lye","year":"2015","journal-title":"EMBO J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.antiviral.2012.04.009","article-title":"A cell free protein fragment complementation assay for monitoring the core interaction of the human cytomegalovirus nuclear egress complex","volume":"95","author":"Schnee","year":"2012","journal-title":"Antiviral. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s12551-019-00570-x","article-title":"Protein-protein interaction modulators: Advances, successes and remaining challenges","volume":"11","author":"Mabonga","year":"2019","journal-title":"Biophys. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/978-981-13-8719-7_13","article-title":"Allosteric Modulators of Protein-Protein Interactions (PPIs)","volume":"1163","author":"Ni","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2165\/00002512-200016020-00005","article-title":"Verteporfin","volume":"16","author":"Scott","year":"2000","journal-title":"Drugs Aging"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wei, C., and Li, X. (2020). Verteporfin inhibits cell proliferation and induces apoptosis in different subtypes of breast cancer cell lines without light activation. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07555-0"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7150\/jca.27472","article-title":"The Efficiency of Verteporfin as a Therapeutic Option in Pre-Clinical Models of Melanoma","volume":"10","author":"Lui","year":"2019","journal-title":"J. Cancer"},{"key":"ref_22","first-page":"CD011821","article-title":"Antiseptics for burns","volume":"7","author":"Norman","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Vachhrajani, V., and Khakhkhar, P. (2020). Antiseptics and Local Antibiotics. Science of Wound Healing and Dressing Materials, Springer Singapore.","DOI":"10.1007\/978-981-32-9236-9"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"213343","DOI":"10.1016\/j.ccr.2020.213343","article-title":"Sulfhydryl groups as targets of mercury toxicity","volume":"417","author":"Ajsuvakova","year":"2020","journal-title":"Coord. Chem. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1128\/AAC.00714-09","article-title":"In vitro activity of thimerosal against ocular pathogenic fungi","volume":"54","author":"Xu","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1002\/jps.3030400509","article-title":"A new mercurial diuretic","volume":"40","author":"Robbins","year":"1951","journal-title":"J. Am. Pharm. Assoc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"7538","DOI":"10.1128\/jvi.66.12.7538-7542.1992","article-title":"Neutralization of diverse human immunodeficiency virus type 1 variants by an anti-V3 human monoclonal antibody","volume":"66","author":"Gorny","year":"1992","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8292","DOI":"10.1002\/chem.201200111","article-title":"A Functionally Selective Synthetic Mimic of the HIV-1 Coreceptor CXCR4","volume":"18","author":"Dietrich","year":"2012","journal-title":"Chem. Eur. J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Gro\u00df, A., M\u00f6bius, K., Hau\u00dfner, C., Donhauser, N., Schmidt, B., and Eichler, J. (2013). Mimicking Protein\u2013Protein Interactions through Peptide\u2013Peptide Interactions: HIV-1 gp120 and CXCR4. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00257"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"H\u00e4ge, S., Sonntag, E., Borst, E.M., Tannig, P., Seyler, L., B\u00e4uerle, T., Bailer, S.M., Lee, C.-P., M\u00fcller, R., and Wangen, C. (2020). Patterns of Autologous and Nonautologous Interactions between Core Nuclear Egress Complex (NEC) Proteins of \u03b1-, \u03b2- and \u03b3-Herpesviruses. Viruses, 12.","DOI":"10.3390\/v12030303"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/3\/471\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:34:53Z","timestamp":1760160893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/3\/471"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":30,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["v13030471"],"URL":"https:\/\/doi.org\/10.3390\/v13030471","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]}}}