Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity

Area of Science:

• Virology
• Drug Discovery
• Immunology

Background:

• Host-directed antivirals (HDAs) offer broad-spectrum activity and a high barrier to resistance.
• Dual-targeting HDAs disrupt multiple viral replication pathways simultaneously.
• Izumerogant (IMU-935) targets RORγ1 and DHODH, host proteins crucial for viral replication.

Purpose of the Study:

• To synthesize and characterize optimized derivatives of izumerogant.
• To evaluate the broad-spectrum antiviral activity of RORγ/DHODH dual inhibitors.
• To elucidate the mechanistic basis for the potent antiviral effects of dual-targeting HDAs.

Main Methods:

• Synthesis of optimized izumerogant derivatives.
• Cell culture-based infection models for diverse human viruses (DNA, RNA, retroviruses).
• Metabolite supplementation assays to compare single-target vs. dual-target inhibition.

Main Results:

• RORγ/DHODH dual inhibitors demonstrated high potency and broad-spectrum activity at nanomolar concentrations.
• Dual-targeting was confirmed as the mechanistic basis for potent antiviral effects.
• An optimized dual inhibitor blocked SARS-CoV-2 replication and showed synergy with molnupiravir in vitro and in vivo.

Conclusions:

• Izumerogant-like dual-targeting HDAs possess potent broad-spectrum antiviral activity.
• These compounds represent promising candidates for clinical development against viral infections.
• Dual-targeting HDAs offer a viable strategy for antiviral therapy and pandemic preparedness.