Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Viruses rely on host cell machinery for replication.
• Host proteins repurposed by viruses can become functionally impaired, termed viral-induced hypomorphs.
• Synthetic lethal (SL) interactions are a validated therapeutic strategy for targeting cancer cells with loss-of-function mutations.

Purpose of the Study:

• To explore the concept of targeting viral-induced hypomorphs as a host-based antiviral strategy.
• To identify SL partners of GBF1, a host protein crucial for many RNA virus infections.
• To validate ARF1 as a potential therapeutic target in the context of poliovirus infection.

Main Methods:

• Utilized a screening approach to identify synthetic lethal (SL) partners of the host protein GBF1.
• Investigated the effect of disrupting identified SL partners on cells expressing viral proteins.
• Employed poliovirus 3A protein and replicon systems to model viral-induced hypomorph formation.

Main Results:

• Identified ARF1 as a top synthetic lethal (SL) partner of GBF1.
• Disruption of ARF1 selectively killed cells synthesizing poliovirus 3A protein or a poliovirus replicon.
• Demonstrated that viral protein interactions can induce host cell vulnerabilities exploitable by targeted drug intervention.

Conclusions:

• Viral protein interactions can create exploitable host cell vulnerabilities (viral-induced hypomorphs).
• Targeting synthetic lethal interactions of these hypomorphs represents a promising host-based antiviral therapeutic approach.
• This strategy holds potential for developing broad-spectrum antivirals effective against diverse viruses, including SARS-CoV-2.