Molecular investigation of the nuclear receptor RORγ1: virus-supportive functions, mechanistic properties, and accessibility for inhibitory small molecules

• Applicant: Privatdozent Dr. Friedrich Hahn
• Subject Area: Virology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575940616

Numerous viruses, including the human cytomegalovirus (HCMV) or SARS-CoV-2, significantly modulate the metabolism of the host cell to promote their own replication. The nuclear receptor RORγ1, a transcription factor that was originally described in the context of immune regulation but also influences central metabolic pathways, plays a role that is still poorly understood. Initial studies show that inhibition of RORγ1 can suppress the replication of various viruses. This proposal aims to systematically investigate the role of RORγ1 in the context of viral infections. The focus is on three questions: (1) Which partner proteins form functional complexes with RORγ1 in virus-infected cells? (2) Which metabolic processes are regulated by RORγ1 and how does this influence virus replication? (3) How accessible is RORγ1 for pharmacological interventions with small molecules? The enzyme function of dihydroorotate dehydrogenase (DHODH), a key enzyme in nucleotide synthesis that is already being investigated in clinical trials with antiviral substances, is being considered as a further target structure. New substances that inhibit both RORγ1 and DHODH simultaneously have proven to be particularly effective. These so-called dual inhibitors will also be investigated in this project. The aim of the project is to gain a deeper understanding of the role of RORγ1 in viral infections. The findings should contribute to the development of new, host-directed antiviral strategies that could be broadly effective against various viruses, an approach that is particularly relevant regarding future pandemics.

• DFG Programme: Research Grants