Multiformin-Type Azaphilones Prevent SARS-CoV-2 Binding to ACE2 Receptor

Area of Science:

• Natural Product Chemistry
• Virology
• Drug Discovery

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) utilizes its spike protein to bind the human Angiotensin-Converting Enzyme 2 (ACE2) receptor for cell entry.
• Identifying inhibitors of this interaction is crucial for developing antiviral therapies.

Purpose of the Study:

• To identify and characterize fungal natural products that inhibit SARS-CoV-2 spike protein binding to ACE2.
• To evaluate the antiviral activity of identified azaphilones in a cell-based infection model.

Main Methods:

• Protein microarray screening to identify inhibitors of spike protein-ACE2 interaction.
• Structure elucidation of new and known azaphilones.
• Cell-based infection assays using SARS-CoV-2 pseudotyped lentivirus particles and Calu-3 cells.

Main Results:

• Azaphilone compounds from fungi were identified as potent inhibitors of SARS-CoV-2 spike protein binding to ACE2.
• Cohaerin F demonstrated significant reduction (>50%) in spike protein-ACE2 binding.
• Several cohaerin and multiformin azaphilones (e.g., Multiformin C and G) nearly abolished viral infection in cell-based assays.

Conclusions:

• Multiformin-type azaphilones effectively prevent SARS-CoV-2 entry by inhibiting spike protein-ACE2 receptor binding.
• These findings highlight the therapeutic potential of fungal azaphilones against SARS-CoV-2 infection.