Potential Beneficial Role of Nitric Oxide in SARS-CoV-2 Infection: Beyond Spike-Binding Inhibition
Sergio Sánchez-García, Antonio Castrillo, Lisardo Boscá, Patricia Prieto
Antioxidants, doi:10.3390/antiox13111301
SARS-CoV-2, the causative virus for the COVID-19 disease, uses its spike glycoprotein to bind to human ACE2 as a first step for viral entry into the cell. For this reason, great efforts have been made to find mechanisms that disrupt this interaction, avoiding the infection. Nitric oxide (NO) is a soluble endogenous gas with known antiviral and immunomodulatory properties. In this study, we aimed to test whether NO could inhibit the binding of the viral spike to ACE2 in human cells and its effects on ACE2 enzymatic activity. Our results show that ACE2 activity was decreased by the NO donors DETA-NONOate and GSNO and by the NO byproduct peroxynitrite. Furthermore, we found that DETA-NONOate could break the spike-ACE2 interaction using the spike from two different variants (Alpha and Gamma) and in two different human cell types. Moreover, the same result was obtained when using NO-producing murine macrophages, while no significant changes were observed in ACE2 expression or distribution within the cell. These results support that it is worth considering NO as a therapeutic agent for COVID-19, as previous reports have suggested.
Supplementary Materials: The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/antiox13111301/s1 , Figure S1 : NO donors and peroxynitrite inhibit the activity of recombinant human ACE2 (extended); Figure S2 : A549-ACE2 and HepG2 cells express ACE2 protein; Figure S3 : GSNO inhibits the binding of the recombinant Gamma variant of the SARS-CoV-2 spike to A549-ACE2 cells; Figure S4 Funding: This research was funded by PID2023-148933OB-I00 and PID2022-137696OB-I00 from MICIN/AEI 13039/501100011033 and the Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CB16/11/00222) from the Instituto de Salud Carlos III (co-financed by the European Development Regional Fund "A Way to Achieve Europe", by the "European Union" and by the "European Union NextGeneration EU/PRTR"), Comunidad de Madrid, Programa Biociencias (S2022-BMD-7223). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).
Institutional Review Board
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"abstract": "<jats:p>SARS-CoV-2, the causative virus for the COVID-19 disease, uses its spike glycoprotein to bind to human ACE2 as a first step for viral entry into the cell. For this reason, great efforts have been made to find mechanisms that disrupt this interaction, avoiding the infection. Nitric oxide (NO) is a soluble endogenous gas with known antiviral and immunomodulatory properties. In this study, we aimed to test whether NO could inhibit the binding of the viral spike to ACE2 in human cells and its effects on ACE2 enzymatic activity. Our results show that ACE2 activity was decreased by the NO donors DETA-NONOate and GSNO and by the NO byproduct peroxynitrite. Furthermore, we found that DETA-NONOate could break the spike–ACE2 interaction using the spike from two different variants (Alpha and Gamma) and in two different human cell types. Moreover, the same result was obtained when using NO-producing murine macrophages, while no significant changes were observed in ACE2 expression or distribution within the cell. These results support that it is worth considering NO as a therapeutic agent for COVID-19, as previous reports have suggested.</jats:p>",
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