The conserved core nuclear egress complex (NEC) as an antiherpesviral drug target

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Julia Tillmanns, Verena Battisti, Jintawee Kicuntod, Friedrich Hahn, Debora Obergfäll, Pia Geiger, Sabrina Wagner, Helmut Buschmann, Bernhard Lesch, Peter Lischka, Heinrich Sticht, Thierry Langer, Manfred Marschall

Published: 01 Jul 2025, Last Modified: 22 Jan 2026Antiviral ResearchEveryoneRevisionsBibTeXCC BY-SA 4.0
Abstract: The nucleocytoplasmic capsid egress of herpesviruses is a uniquely regulated process. As well-established for the human cytomegalovirus (HCMV) core nuclear egress complex (NEC), the pUL50–pUL53 NEC heterodimer oligomerizes and builds hexameric lattices for the regulated nucleocytoplasmic release of viral capsids. Recently, we and others validated the NEC as a novel target for antiviral strategies. So far, the experimental targeting approaches included the development of NEC-directed small molecules, cell-penetrating peptides, NEC-specific mutagenesis, and the expression of NEC-interfering protein constructs. Our current postulate states that a small molecule-mediated interference with the assembly of the core NEC prevents NEC-dependent egress regulation and thereby strictly limits viral replication. Here, we present an experimental proof of this antiviral strategy, and the data provide evidence for the following points: (i) pharmacophore-based approaches demonstrated to be successful in the identification of NEC-specific inhibitory small molecules, (ii) already a low number of 36 analyzed small molecules yielded eight experimental hits with micromolar to submicromolar antiviral activity, (iii) their antiviral potency was asserted to the predicted NEC-interfering mode-of-action, (iv) two identified hit compounds presented a broad antiherpesviral activity, and (v) a further pharmacophore-assisted refinement of NEC-directed molecules may lead to the development of highly effective and even broadly acting antivirals. Combined, we strengthen the recently postulated potential of the NEC as a next-generation antiherpesviral drug target by identifying broadly active NEC inhibitors via a pharmacophore-based approach.