Targeting the Spike: Repurposing Mithramycin and Dihydroergotamine to Block SARS-CoV-2 Infection

Area of Science:

• Virology
• Drug Discovery
• Structural Biology

Background:

• Current SARS-CoV-2 vaccines face challenges from emerging variants.
• Complementary therapies are needed to combat SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2).

Purpose of the Study:

• To identify small compounds that inhibit SARS-CoV-2 entry by targeting the spike protein's Receptor Binding Domain (RBD).
• To investigate the potential of repurposing existing FDA-approved drugs as SARS-CoV-2 treatments.

Main Methods:

• In silico screening of small compounds against the SARS-CoV-2 spike protein RBD.
• Cell-based assays to evaluate the antiviral activity of identified compounds.
• STD-NMR (Saturation Transfer Difference Nuclear Magnetic Resonance) spectroscopy to confirm drug-target interactions.

Main Results:

• Two FDA-approved drugs, mithramycin and dihydroergotamine, were identified as potential inhibitors.
• These compounds effectively blocked SARS-CoV-2 infection in cell-based assays at micromolar concentrations.
• STD-NMR experiments provided evidence for direct interaction between dihydroergotamine and the spike protein.

Conclusions:

• Mithramycin and dihydroergotamine show promise for repurposing as antiviral therapies against SARS-CoV-2.
• Targeting the RBD with small molecules offers a potential strategy to prevent viral entry.
• Further clinical investigation of these compounds for SARS-CoV-2 treatment is warranted.