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Properties of Oligomeric Interaction of the Cytomegalovirus Core Nuclear Egress Complex (NEC) and Its Sensitivity to an NEC Inhibitory Small Molecule
Article

Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors

1
Division of Medicinal Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg (FAU), 91058 Erlangen, Germany
2
Institute for Clinical and Molecular Virology, University of Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
3
Division of Biotechnology, Department of Biology, University of Erlangen-Nürnberg (FAU), 91052 Erlangen, Germany
4
AiCuris Anti-Infective Cures GmbH, 42117 Wuppertal, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Elke Bogner
Viruses 2021, 13(3), 471; https://doi.org/10.3390/v13030471
Received: 15 February 2021 / Revised: 8 March 2021 / Accepted: 9 March 2021 / Published: 12 March 2021
(This article belongs to the Special Issue New Concepts of Antiviral Strategies Against HCMV)
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® 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–protein 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. View Full-Text
Keywords: human cytomegalovirus; nuclear egress complex (NEC); core NEC inhibitor; antiviral activity; small molecule inhibitor human cytomegalovirus; nuclear egress complex (NEC); core NEC inhibitor; antiviral activity; small molecule inhibitor
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MDPI and ACS Style

Alkhashrom, S.; Kicuntod, J.; Häge, S.; Schweininger, J.; Muller, Y.A.; Lischka, P.; Marschall, M.; Eichler, J. Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors. Viruses 2021, 13, 471. https://doi.org/10.3390/v13030471

AMA Style

Alkhashrom S, Kicuntod J, Häge S, Schweininger J, Muller YA, Lischka P, Marschall M, Eichler J. Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors. Viruses. 2021; 13(3):471. https://doi.org/10.3390/v13030471

Chicago/Turabian Style

Alkhashrom, Sewar, Jintawee Kicuntod, Sigrun Häge, Johannes Schweininger, Yves A. Muller, Peter Lischka, Manfred Marschall, and Jutta Eichler. 2021. "Exploring the Human Cytomegalovirus Core Nuclear Egress Complex as a Novel Antiviral Target: A New Type of Small Molecule Inhibitors" Viruses 13, no. 3: 471. https://doi.org/10.3390/v13030471

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