Repurposing Niclosamide as a Novel Anti-SARS-CoV-2 Drug by Restricting Entry Protein CD147

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• The COVID-19 pandemic caused by SARS-CoV-2 necessitates new therapeutic strategies due to viral mutations challenging existing treatments.
• The CD147-spike protein interaction is an alternative entry pathway for SARS-CoV-2 into host cells, making CD147 a potential therapeutic target.
• Understanding the regulation of CD147 is crucial for developing effective COVID-19 treatments.

Purpose of the Study:

• To investigate the role of Human-antigen R (HuR) in the post-transcriptional regulation of CD147.
• To explore the potential of niclosamide as a therapeutic agent against SARS-CoV-2 by targeting the HuR-CD147 pathway.
• To elucidate the mechanism by which niclosamide affects CD147 expression and SARS-CoV-2 infection.

Main Methods:

• Demonstrated HuR binding to the 3'-untranslated region (UTR) of CD147 mRNA.
• Assessed CD147 levels in cell lines following HuR depletion.
• Investigated the effect of niclosamide on HuR translocation, CD147 glycosylation, and SARS-CoV-2 infection in A549 cells.

Main Results:

• HuR directly binds to the CD147 3'-UTR, regulating its expression.
• Depletion of HuR led to decreased CD147 levels in multiple cell lines.
• Niclosamide reduced CD147 by inhibiting HuR cytoplasmic translocation and CD147 glycosylation.
• SARS-CoV-2 infection upregulated CD147 in A549 cells, an effect neutralized by niclosamide in a dose-dependent manner.

Conclusions:

• HuR is a key regulator of CD147 expression.
• Niclosamide effectively reduces CD147 levels and viral entry, presenting a promising therapeutic strategy for COVID-19.
• Targeting the HuR-CD147 pathway offers a novel approach to combat SARS-CoV-2 infection.