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Potential Beneficial Role of Nitric Oxide in SARS-CoV-2 Infection: Beyond Spike-Binding Inhibition

Sánchez-García et al., Antioxidants, doi:10.3390/antiox13111301
Oct 2024  
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In Vitro study showing that nitric oxide (NO) inhibits SARS-CoV-2 spike protein binding to ACE2 and reduces ACE2 enzymatic activity. Authors showed that NO donors DETA-NONOate (DETA-NO) and S-nitrosoglutathione (GSNO) significantly decreased ACE2 activity, with GSNO showing stronger inhibition comparable to the specific ACE2 inhibitor MLN-4760. The binding of both alpha and gamma variants of SARS-CoV-2 spike protein was reduced by NO donors in HepG2 cells and ACE2-transfected A549 lung epithelial cells, without affecting cell viability. Using a co-culture system with murine peritoneal macrophages stimulated to produce NO, authors confirmed that endogenous NO production also inhibited spike protein binding to ACE2. The study utilized multiple experimental approaches to validate NO's effects: recombinant protein assays for ACE2 activity, flow cytometry for spike binding, and immunofluorescence for ACE2 expression. NO's dual action of inhibiting both ACE2 activity and spike protein binding suggests potential therapeutic applications for COVID-19.
2 preclinical studies support the efficacy of nitric oxide for COVID-19:
Sánchez-García et al., 26 Oct 2024, peer-reviewed, 4 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperNitric OxideAll
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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>', 'DOI': '10.3390/antiox13111301', 'type': 'journal-article', 'created': { 'date-parts': [[2024, 10, 28]], 'date-time': '2024-10-28T08:15:02Z', 'timestamp': 1730103302000}, 'page': '1301', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Potential Beneficial Role of Nitric Oxide in SARS-CoV-2 Infection: Beyond Spike-Binding ' 'Inhibition', 'prefix': '10.3390', 'volume': '13', 'author': [ { 'ORCID': 'http://orcid.org/0000-0002-3332-7603', 'authenticated-orcid': False, 'given': 'Sergio', 'family': 'Sánchez-García', 'sequence': 'first', 'affiliation': [ { 'name': 'Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, ' 'Arturo Duperier 4, 28029 Madrid, Spain'}]}, { 'given': 'Antonio', 'family': 'Castrillo', 'sequence': 'additional', 'affiliation': [ { 'name': 'Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, ' 'Arturo Duperier 4, 28029 Madrid, Spain'}, { 'name': 'Unidad de Biomedicina (Unidad Asociada al CSIC), Universidad de ' 'Las Palmas de Gran Canaria, 35016 Las Palmas, Spain'}]}, { 'ORCID': 'http://orcid.org/0000-0002-0253-5469', 'authenticated-orcid': False, 'given': 'Lisardo', 'family': 'Boscá', 'sequence': 'additional', 'affiliation': [ { 'name': 'Instituto de Investigaciones Biomédicas Sols-Morreale, CSIC-UAM, ' 'Arturo Duperier 4, 28029 Madrid, Spain'}, { 'name': 'Centro de Investigación Biomédica en Red de Enfermedades ' 'Cardiovasculares (CIBERCV), Av. 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