Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity

Area of Science:

• Virology
• Drug Discovery
• Molecular Biology

Background:

• Host-directed therapeutics are crucial for combating viral pandemics.
• Apratoxin S4 (Apra S4) inhibits Sec61, impacting protein translocation into the endoplasmic reticulum (ER).
• Sec61 is a vital host factor for viral proteostasis.

Purpose of the Study:

• To evaluate Apratoxin S4 (Apra S4) as a broad-spectrum antiviral agent.
• To investigate the efficacy of Apra S4 against SARS-CoV-2, influenza A virus, and flaviviruses.
• To characterize the mechanism of action of Apra S4 in viral infections.

Main Methods:

• Cellular models of viral infection (SARS-CoV-2, influenza A, Zika, West Nile, Dengue).
• Concentration-dependent inhibition assays.
• Transmission electron microscopy (TEM).
• Analysis of viral RNA, protein production, and secretory protein trafficking.

Main Results:

• Apra S4 demonstrated potent, concentration-dependent inhibition of viral replication.
• Subnanomolar activity was observed against SARS-CoV-2 and influenza A virus in human cells.
• Apra S4 blocked the formation of double-membrane vesicles essential for viral replication.
• The drug reduced dsRNA formation and inhibited viral protein production and spike protein trafficking.

Conclusions:

• Apratoxin S4 exhibits potent and broad-spectrum antiviral activity, particularly against SARS-CoV-2 and influenza A virus.
• Apra S4 acts at a post-entry stage, interfering with viral replication machinery.
• Sec61 inhibitors represent a promising class of host-directed antivirals warranting further investigation.