| Affiliation: | 1. Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany;2. Computational Biochemistry, Center of Medical Biotechnology, University of Duisburg-Essen, Essen, Germany;3. Infection Biology Unit, German Primate Center-Leibniz Institute for Primate Research, Göttingen, Germany Faculty of Biology and Psychology, Georg-August-University, Göttingen, Germany;4. Infection Biology Unit, German Primate Center-Leibniz Institute for Primate Research, Göttingen, Germany;5. Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, Tübingen, Germany;6. Institute for Microbiology and Hygiene, Ulm University Medical Center, Ulm, Germany |
| Abstract: | Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored. |
