Host protein ARF1 is a proviral factor for SARS-CoV-2 and a candidate broad-spectrum therapeutic target

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) assembly occurs at the ER-Golgi intermediate compartment (ERGIC).
• The viral membrane (M) protein is central to SARS-CoV-2 assembly in the ERGIC, but host factors facilitating its concentration are unknown.
• Identifying host factors involved in viral assembly could reveal broad-spectrum antiviral targets.

Purpose of the Study:

• To identify host factors interacting with the SARS-CoV-2 M protein.
• To investigate the role of identified host factors in viral propagation and pathogenicity.
• To explore the therapeutic potential of targeting the host-viral protein interaction.

Main Methods:

• Co-immunoprecipitation to identify M-interacting proteins.
• Cell-based assays to assess viral propagation upon host factor manipulation.
• Pharmacological inhibition of identified host factors using small molecules and peptidomimetics.
• In vivo studies using K18-hACE2 mouse model to evaluate therapeutic efficacy.

Main Results:

• ARF1 was identified as a host protein interacting with the SARS-CoV-2 M protein.
• ARF1 facilitates M protein accumulation in the ERGIC, enhancing virion production.
• Pharmacological inhibition of ARF1 disrupted viral assembly and propagation in vitro and reduced viral load and pathogenicity in vivo.
• A peptidomimetic inhibitor targeting the ARF1-M interaction demonstrated therapeutic efficacy in a mouse model.

Conclusions:

• ARF1 is a proviral host factor critical for SARS-CoV-2 assembly and propagation.
• Targeting ARF1 or the ARF1-M interaction interface offers a promising strategy for developing broad-spectrum SARS-CoV-2 therapeutics.
• Inhibition of ARF1 can effectively block viral assembly, propagation, and reduce disease severity.