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Thiol drugs may also alter the redox status of the cysteine-rich SARS-CoV-2 spike glycoprotein (SARS-2-S) and thereby disrupt ACE2 binding. Using ACE2 binding assay, reporter virus pseudotyped with SARS-CoV-2 spikes (ancestral and variants) and authentic SARS-CoV-2 (Wuhan-1), we find that multiple thiol drugs inhibit SARS-2-S binding to ACE2 and virus entry into cells. Pseudoviruses carrying variant spikes were less efficiently inhibited as compared to pseudotypes bearing an ancestral spike, but the most potent drugs still inhibited the Delta variant in the low millimolar range. IC50 values followed the order of their cystine cleavage rates and lower thiol pKa values. In hamsters infected with SARS-CoV-2, intraperitoneal (IP) cysteamine decreased neutrophilic inflammation and alveolar hemorrhage in the lungs but did not decrease viral infection, most likely because IP delivery could not achieve millimolar concentrations in the airways. These data show that thiol drugs inhibit SARS-CoV-2 infection\n                  <jats:italic>in vitro<\/jats:italic>\n                  and reduce SARS-CoV-2-related lung injury\n                  <jats:italic>in vivo<\/jats:italic>\n                  and provide strong rationale for trials of systemically delivered thiol drugs as COVID-19 treatments. We propose that antiviral effects of thiol drugs\n                  <jats:italic>in vivo<\/jats:italic>\n                  will require delivery directly to the airways to ensure millimolar drug concentrations and that thiol drugs with lower thiol pKa values are most likely to be effective.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary<\/jats:title>\n                  <jats:p>\n                    The effect of cysteamine to decrease SARS-CoV-2 pneumonia\n                    <jats:italic>in vivo<\/jats:italic>\n                    and of multiple thiol drugs to inhibit SARS-CoV-2 infection\n                    <jats:italic>in vitro<\/jats:italic>\n                    provides rationale for clinical trials of thiol drugs in COVID-19.\n                  <\/jats:p>\n                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