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Background Antivirals are needed to combat the COVID-19 pandemic, which is caused by SARS-CoV-2. The clinically-proven protease inhibitor Camostat mesylate inhibits SARS-CoV-2 infection by blocking the virus-activating host cell protease TMPRSS2. However, antiviral activity of Camostat mesylate metabolites and potential viral resistance have not been analyzed. Moreover, antiviral activity of Camostat mesylate in human lung tissue remains to be demonstrated. Methods We used recombinant TMPRSS2, reporter particles bearing the spike protein of SARS-CoV-2 or authentic SARS-CoV-2 to assess inhibition of TMPRSS2 and viral entry, respectively, by Camostat mesylate and its metabolite GBPA. Findings We show that several TMPRSS2-related proteases activate SARS-CoV-2 and that two, TMPRSS11D and TMPRSS13, are robustly expressed in the upper respiratory tract. However, entry mediated by these proteases was blocked by Camostat mesylate. The Camostat metabolite GBPA inhibited recombinant TMPRSS2 with reduced efficiency as compared to Camostat mesylate. In contrast, both inhibitors exhibited similar antiviral activity and this correlated with the rapid conversion of Camostat mesylate into GBPA in the presence of serum. Finally, Camostat mesylate and GBPA blocked SARS-CoV-2 spread in human lung tissue ex vivo and the related protease inhibitor Nafamostat mesylate exerted augmented antiviral activity. Interpretation Our results suggest that SARS-CoV-2 can use TMPRSS2 and closely related proteases for spread in the upper respiratory tract and that spread in the human lung can be blocked by Camostat mesylate and its metabolite GBPA. Funding NIH, Damon Runyon Foundation, ACS, NYCT, DFG, EU, Berlin Mathematics center MATH+, BMBF, Lower Saxony, Lundbeck Foundation, Novo Nordisk Foundation.

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The atom and symmetry specific properties of x-ray emission spectroscopy have been applied to the investigation of CO adsorbed on Ni(100) and Cu(100) surfaces. In comparison to ab initio electronic structure calculations, obtained in density functional theory, we develop a consistent electronic structure model of CO adsorption on transition and noble metals and extend to a conceptual model of the surface chemical bond. A strong CO–substrate interaction is found, characterized by significant hybridization of the initial CO orbitals and the metal bands. In the π system an allylic configuration is found as the result of orbital mixing between the CO 1π, 2π* and the metal dπ-band which is manifested experimentally in the observation of an oxygen lone-pair state. In the σ system experimental evidence of equally strong orbital mixing has been found. Energetically, the adsorbate–substrate complex is stabilized by the π-interaction but is destabilized by the σ-interaction. Furthermore, the internal C–O bond carried by the π-interaction is weakened upon adsorption, which is opposite for the internal C–O σ bond that is strengthened. The equilibrium properties of CO adsorbed on these metals are found to be the direct result of the balance between the σ- and π-interactions; both in terms of the total energy and the local bond properties.

The interplay between the electronic and the geometric structure of adsorbates is of fundamental importance for the understanding of many surface phenomena. Using x-ray emission spectroscopy and ab initio cluster calculations, this issue has been investigated in unprecedented detail for CO adsorption in different adsorption sites. The investigation establishes pi bonding and sigma repulsion, both increasing with the number of coordinated metal atoms. The two contributions partly compensate each other, leading to only small differences in adsorption energies for the different adsorption sites despite very large variations in the electronic structure.