Targeting the host factor HGS-viral membrane protein interaction in coronavirus infection

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Current antiviral therapies predominantly target viral proteins, leaving host-directed strategies underexplored.
• Identifying host factors essential for viral replication is key to developing novel antiviral approaches.

Purpose of the Study:

• To identify host proteins critical for pan-coronavirus infection using genome-wide CRISPRi screening.
• To investigate the mechanism of host factor involvement in viral assembly.
• To discover novel antiviral agents targeting host-viral protein interactions.

Main Methods:

• Genome-wide CRISPRi screening to identify essential host factors.
• Co-immunoprecipitation to confirm protein-protein interactions.
• In vitro and in vivo assays to evaluate antiviral efficacy.
• Drug screening of FDA-approved compounds.

Main Results:

• Hepatocyte Growth Factor-Regulated Tyrosine Kinase Substrate (HGS) was identified as essential for pan-coronavirus infection.
• HGS directly interacts with the viral membrane (M) protein, mediating its trafficking for virion assembly.
• HGS deficiency or disruption of the HGS-M interaction blocks viral assembly by causing M protein retention in the ER.
• Riboflavin tetrabutyrate (RTB) was identified as an FDA-approved drug that disrupts the HGS-M interaction and exhibits broad anti-pan-coronavirus activity.

Conclusions:

• HGS is a druggable host target essential for pan-coronavirus replication.
• Disrupting the HGS-M protein interaction is a viable strategy for broad-spectrum antiviral therapy.
• Riboflavin tetrabutyrate (RTB) shows promise as a novel, broad-spectrum antiviral candidate.