Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein

Area of Science:

• Virology
• Drug Discovery
• Medicinal Chemistry

Background:

• The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global health crisis.
• New SARS-CoV-2 variants and other emerging coronaviruses necessitate broad-spectrum therapeutics.
• Existing treatments require augmentation with effective and versatile antiviral agents.

Purpose of the Study:

• To identify US FDA-approved drugs with potent antiviral activity against SARS-CoV-2 and its variants.
• To investigate the potential of phenothiazine derivatives as broad-spectrum antiviral agents.
• To elucidate the mechanism of action for phenothiazine-mediated inhibition of SARS-CoV-2.

Main Methods:

• Screening of US FDA-approved drugs for antiviral activity.
• Testing inhibition of pseudotyped SARS-CoV-2, variants of concern (Delta, Omicron sublineages XBB, BQ.1.1), SARS-CoV, and MERS-CoV.
• Mechanistic studies to determine the stage of viral infection targeted by phenothiazines.

Main Results:

• Phenothiazine derivatives demonstrated potent inhibition against SARS-CoV-2 pseudovirus and various variants.
• Inhibitory activity was observed against SARS-CoV and MERS-CoV pseudoviruses.
• Phenothiazines appear to inhibit SARS-CoV-2 infection by targeting the spike protein, potentially preventing its cleavage.

Conclusions:

• Phenothiazines exhibit broad-spectrum antiviral activity against SARS-CoV-2, its variants, and other human coronaviruses.
• Phenothiazines represent a promising class of compounds for the development of novel antiviral therapies.
• Further research into phenothiazines could lead to effective treatments for current and future coronavirus outbreaks.