The redox status of the
cysteine-rich SARS-CoV-2 spike
glycoprotein (SARS-2-S) is important for the binding of SARS-2-S to
angiotensin-converting enzyme 2 (ACE2), suggesting that drugs with a functional
thiol group ("
thiol drugs") may cleave cystines to disrupt SARS-CoV-2 cell entry. In addition, neutrophil-induced oxidative stress is a mechanism of
COVID-19 lung injury, and the
antioxidant and anti-inflammatory properties of
thiol drugs, especially
cysteamine, may limit this injury. To first explore the
antiviral effects of
thiol drugs in
COVID-19, we used an ACE-2 binding assay and cell entry assays utilizing reporter pseudoviruses and authentic SARS-CoV-2 viruses. We found that multiple
thiol drugs inhibit SARS-2-S binding to ACE2 and
virus infection. The most potent drugs were effective in the low millimolar range, and IC50 values followed the order of their
cystine cleavage rates and lower
thiol pKa values. To determine if
thiol drugs have
antiviral effects in vivo and to explore any anti-inflammatory effects of
thiol drugs in
COVID-19, we tested the effects of
cysteamine delivered intraperitoneally to hamsters infected with SARS-CoV-2.
Cysteamine did not decrease lung
viral infection, but it significantly decreased lung neutrophilic
inflammation and alveolar
hemorrhage. We speculate that the concentration of
cysteamine achieved in the lungs with intraperitoneal delivery was insufficient for
antiviral effects but sufficient for anti-inflammatory effects. We conclude that
thiol drugs decrease SARS-CoV-2
lung inflammation and injury, and we provide rationale for future studies to test if direct (
aerosol) delivery of
thiol drugs to the airways might also result in
antiviral effects.