Inhibition of coronavirus HCoV-OC43 by targeting the eIF4F complex.

Area of Science:

• Molecular Biology
• Virology
• Drug Discovery

Background:

• The eukaryotic translation initiation factor 4F (eIF4F) complex is crucial for protein synthesis and is implicated in diseases like cancer and infections.
• Coronaviruses depend on eIF4F activity for producing essential viral proteins, making it a potential therapeutic target.
• Existing strategies targeting coronavirus translation often involve repurposing eIF4F inhibitors, with limited success.

Purpose of the Study:

• To identify novel small molecules that disrupt eIF4F complex formation and inhibit coronavirus replication.
• To evaluate the efficacy of identified compounds against human coronavirus OC43 (HCoV-OC43).

Main Methods:

• Conducted a high-throughput screen of 338,000 small molecules to identify inhibitors of eIF4F-driven, cap-dependent translation.
• Assessed the antiviral activity of lead compounds against HCoV-OC43 in infected cell lines (Vero E6, A549).
• Analyzed the impact of compounds on eIF4F complex assembly, viral RNA, protein levels, and host gene expression.

Main Results:

• Identified SBI-1232, SBI-5844, and SBI-0498 as potent inhibitors of HCoV-OC43 with minimal cytotoxicity.
• SBI-5844 and SBI-0498 effectively reversed gene expression changes induced by HCoV-OC43 infection.
• These compounds inhibited eIF4F complex assembly, leading to reduced viral nucleocapsid protein synthesis and lower viral RNA and protein levels.

Conclusions:

• SBI-5844 and SBI-0498 are effective small molecule inhibitors targeting the eIF4F complex.
• These compounds demonstrate potential for limiting coronavirus replication by inhibiting viral protein and RNA production.
• SBI-5844 and SBI-0498 represent promising candidates for developing novel therapeutic strategies against coronaviruses.