2. Academic Validation
  3. Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels

Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels

  • Antiviral Res. 2023 Dec 4:105769. doi: 10.1016/j.antiviral.2023.105769.
Christina Wangen 1,  Andrea Raithel 2,  Julia Tillmanns 3,  Christian Gege 4,  Alexandra Herrmann 5,  Daniel Vitt 6,  Hella Kohlhof 7,  Manfred Marschall 8,  Friedrich Hahn 9
Affiliations

Affiliations

  • 1 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: christina.wangen@uk-erlangen.de.
  • 2 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: andrea.raithel@fau.de.
  • 3 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: jul.tillmanns@fau.de.
  • 4 Immunic AG, Gräfelfing, Germany. Electronic address: christian.gege@imux.com.
  • 5 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Immunic AG, Gräfelfing, Germany. Electronic address: alexandra.herrmann@imux.com.
  • 6 Immunic AG, Gräfelfing, Germany. Electronic address: daniel.vitt@imux.com.
  • 7 Immunic AG, Gräfelfing, Germany. Electronic address: hella.kohlhof@imux.com.
  • 8 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: manfred.marschall@fau.de.
  • 9 Institute for Clinical and Molecular Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: friedrich.hahn@uk-erlangen.de.
PMID: 38056603 DOI: 10.1016/j.antiviral.2023.105769
Abstract

Currently, the clinically approved repertoire of Antiviral drugs predominantly comprises direct-acting antivirals (DAAs). However, the use of DAAs is frequently limited by adverse effects, restriction to individual virus species, or the induction of viral drug resistance. These issues will likely be resolved by the introduction of host-directed antivirals (HDAs) targeting cellular proteins crucial for viral replication. However, experiences with the development of Antiviral HDAs and clinical applications are still in their infancy. With the present study, we explored the human nuclear receptor and transcription factor RORγ isoform 1 (RORγ1), a member of the retinoic acid receptor-related orphan receptor (ROR) family, as a putative target of Antiviral HDAs. To this end, Cell Culture models were used to investigate major viral human pathogens, i.e. the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human cytomegalovirus (HCMV), varicella zoster virus (VZV) and human immunodeficiency virus 1 (HIV-1). Our results demonstrated (i) an Antiviral activity of the clinically relevant RORγ modulators cedirogant and Others, (ii) that isoform RORγ1 acts as the responsible determinant and drug target in the analyzed cell culture-based models, (iii) a selectivity of the Antiviral effect for RORγ1 over related receptors RORα and RORβ, (iv) a late-phase inhibition exerted by cedirogant in HCMV replication and (v) a mechanistic link to the cellular Cholesterol biosynthesis. Combined, the data highlight this novel RORγ-specific Antiviral targeting concept and the developmental potential of RORγ-directed small molecules.

Keywords

Host-directed antiviral targeting; Major viral human pathogens; Metabolic restriction of virus replication; Novel drug targeting options; RORγ2/t modulator cedirogant; Transcriptional regulation of cholesterol biosynthesis.

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