Thiol drugs decrease SARS-CoV-2 lung injury in vivo and disrupt SARS-CoV-2 spike complex binding to ACE2 in vitro.

Area of Science:

• Biochemistry
• Virology
• Pulmonology

Background:

• Neutrophil-driven oxidative stress contributes to COVID-19 lung injury.
• Thiol drugs possess antioxidant and anti-inflammatory properties.
• Thiol drugs may interfere with SARS-CoV-2 spike (SARS-2-S) glycoprotein binding to ACE2.

Approach:

• Utilized ACE2 binding assays, pseudotyped viruses (ancestral and variants), and authentic SARS-CoV-2 (Wuhan-1).
• Assessed inhibition of SARS-2-S binding to ACE2 and viral entry.
• Evaluated cysteamine's efficacy in a hamster model of SARS-CoV-2 infection.

Key Points:

• Multiple thiol drugs inhibited SARS-2-S binding to ACE2 and viral entry *in vitro*.
• Inhibition was more potent against ancestral spikes than variants, with Delta variant inhibition in the low millimolar range.
• Drug efficacy correlated with cystine cleavage rates and lower thiol pKa values.
• Intraperitoneal cysteamine reduced lung inflammation and hemorrhage in hamsters but not viral load, likely due to insufficient airway concentrations.

Conclusions:

• Thiol drugs demonstrate *in vitro* inhibition of SARS-CoV-2 and *in vivo* reduction of COVID-19-related lung injury.
• Effective *in vivo* antiviral activity necessitates direct airway delivery to achieve millimolar concentrations.
• Thiol drugs with lower thiol pKa values are predicted to be more effective.