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

Wangen C, Raithel A, Tillmanns J, Gege C, Herrmann A, Vitt D, Kohlhof H, Marschall M, Hahn F (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Antiviral Research Elsevier Masson

Book Volume: 221

Article Number: 105769

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.

Authors with CRIS profile

Julia Tillmanns Institute of Clinical and Molecular Virology Alexandra Herrmann Institute of Clinical and Molecular Virology Manfred Marschall Medizinische Fakultät Friedrich Hahn Institute of Clinical and Molecular Virology

Involved external institutions

Immunic AG DE Germany (DE)

How to cite

APA:

Wangen, C., Raithel, A., Tillmanns, J., Gege, C., Herrmann, A., Vitt, D.,... Hahn, F. (2024). Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels. Antiviral Research, 221. https://dx.doi.org/10.1016/j.antiviral.2023.105769

MLA:

Wangen, Christina, et al. "Validation of nuclear receptor RORγ isoform 1 as a novel host-directed antiviral target based on the modulation of cholesterol levels." Antiviral Research 221 (2024).

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