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Zn2+ and Cu2+ Interaction with the Recognition Interface of ACE2 for SARS-CoV-2 Spike Protein

Pelucelli et al., International Journal of Molecular Sciences, doi:10.3390/ijms24119202, May 2023
https://c19early.org/pelucelli.html
Zinc for COVID-19
2nd treatment shown to reduce risk in July 2020, now with p = 0.00000028 from 47 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments.
6,000+ studies for 175 treatments. c19early.org
In Vitro biochemical study showing that zinc and copper ions bind to peptide fragments from the ACE2 recognition interface for SARS-CoV-2 spike protein. The results suggest that zinc and copper could potentially reduce spike binding affinity and therefore SARS-CoV-2 infection by altering ACE2 receptor conformation.
11 preclinical studies support the efficacy of zinc for COVID-19:
Pelucelli et al., 24 May 2023, peer-reviewed, 7 authors. Contact: peana@uniss.it (corresponding author), alessiopelucelli@gmail.com, sere@uniss.it, zoroddu@uniss.it, bartosz.orzel@chem.uni.wroc.pl, elzbieta.gumienna-kontecka@chem.uni.wroc.pl.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Zn2+ and Cu2+ Interaction with the Recognition Interface of ACE2 for SARS-CoV-2 Spike Protein
Alessio Pelucelli, Massimiliano Peana, Bartosz Orzeł, Karolina Piasta, Elzbieta Gumienna-Kontecka, Serenella Medici, Maria Antonietta Zoroddu
International Journal of Molecular Sciences, doi:10.3390/ijms24119202
The spike protein (S) of SARS-CoV-2 is able to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor with a much higher affinity compared to other coronaviruses. The binding interface between the ACE2 receptor and the spike protein plays a critical role in the entry mechanism of the SARS-CoV-2 virus. There are specific amino acids involved in the interaction between the S protein and the ACE2 receptor. This specificity is critical for the virus to establish a systemic infection and cause COVID-19 disease. In the ACE2 receptor, the largest number of amino acids playing a crucial role in the mechanism of interaction and recognition with the S protein is located in the C-terminal part, which represents the main binding region between ACE2 and S. This fragment is abundant in coordination residues such as aspartates, glutamates, and histidine that could be targeted by metal ions. Zn 2+ ions bind to the ACE2 receptor in its catalytic site and modulate its activity, but it could also contribute to the structural stability of the entire protein. The ability of the human ACE2 receptor to coordinate metal ions, such as Zn 2+ , in the same region where it binds to the S protein could have a crucial impact on the mechanism of recognition and interaction of ACE2-S, with consequences on their binding affinity that deserve to be investigated. To test this possibility, this study aims to characterize the coordination ability of Zn 2+ , and also Cu 2+ for comparison, with selected peptide models of the ACE2 binding interface using spectroscopic and potentiometric techniques.
Conflicts of Interest: The authors declare no conflict of interest.
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DOI record: { "DOI": "10.3390/ijms24119202", "ISSN": [ "1422-0067" ], "URL": "http://dx.doi.org/10.3390/ijms24119202", "abstract": "<jats:p>The spike protein (S) of SARS-CoV-2 is able to bind to the human angiotensin-converting enzyme 2 (ACE2) receptor with a much higher affinity compared to other coronaviruses. The binding interface between the ACE2 receptor and the spike protein plays a critical role in the entry mechanism of the SARS-CoV-2 virus. There are specific amino acids involved in the interaction between the S protein and the ACE2 receptor. This specificity is critical for the virus to establish a systemic infection and cause COVID-19 disease. In the ACE2 receptor, the largest number of amino acids playing a crucial role in the mechanism of interaction and recognition with the S protein is located in the C-terminal part, which represents the main binding region between ACE2 and S. This fragment is abundant in coordination residues such as aspartates, glutamates, and histidine that could be targeted by metal ions. Zn2+ ions bind to the ACE2 receptor in its catalytic site and modulate its activity, but it could also contribute to the structural stability of the entire protein. The ability of the human ACE2 receptor to coordinate metal ions, such as Zn2+, in the same region where it binds to the S protein could have a crucial impact on the mechanism of recognition and interaction of ACE2–S, with consequences on their binding affinity that deserve to be investigated. To test this possibility, this study aims to characterize the coordination ability of Zn2+, and also Cu2+ for comparison, with selected peptide models of the ACE2 binding interface using spectroscopic and potentiometric techniques.</jats:p>", "alternative-id": [ "ijms24119202" ], "author": [ { "ORCID": "https://orcid.org/0000-0002-9502-7585", "affiliation": [ { "name": "Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy" } ], "authenticated-orcid": false, "family": "Pelucelli", "given": "Alessio", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0002-3306-0419", "affiliation": [ { "name": "Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy" } ], "authenticated-orcid": false, "family": "Peana", "given": "Massimiliano", "sequence": "additional" }, { "affiliation": [ { "name": "Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland" } ], "family": "Orzeł", "given": "Bartosz", "sequence": "additional" }, { "affiliation": [ { "name": "Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland" } ], "family": "Piasta", "given": "Karolina", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-9556-6378", "affiliation": [ { "name": "Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland" } ], "authenticated-orcid": false, "family": "Gumienna-Kontecka", "given": "Elzbieta", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0002-4304-0251", "affiliation": [ { "name": "Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy" } ], "authenticated-orcid": false, "family": "Medici", "given": "Serenella", "sequence": "additional" }, { "ORCID": "https://orcid.org/0000-0001-9583-4750", "affiliation": [ { "name": "Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, 07100 Sassari, Italy" } ], "authenticated-orcid": false, "family": "Zoroddu", "given": "Maria Antonietta", "sequence": "additional" } ], "container-title": "International Journal of Molecular Sciences", "container-title-short": "IJMS", "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2023, 5, 25 ] ], "date-time": "2023-05-25T06:58:48Z", "timestamp": 1684997928000 }, "deposited": { "date-parts": [ [ 2025, 1, 15 ] ], "date-time": "2025-01-15T13:35:03Z", "timestamp": 1736948103000 }, "funder": [ { "award": [ "UA2002DOTTRIC2021 articolo 9, comma 3, D.M. 8 febbraio 2013, n. 45" ], "name": "Progetto" } ], "indexed": { "date-parts": [ [ 2025, 6, 27 ] ], "date-time": "2025-06-27T07:32:08Z", "timestamp": 1751009528417, "version": "3.37.3" }, "is-referenced-by-count": 4, "issue": "11", "issued": { "date-parts": [ [ 2023, 5, 24 ] ] }, "journal-issue": { "issue": "11", "published-online": { "date-parts": [ [ 2023, 6 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0/", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2023, 5, 24 ] ], "date-time": "2023-05-24T00:00:00Z", "timestamp": 1684886400000 } } ], "link": [ { "URL": "https://www.mdpi.com/1422-0067/24/11/9202/pdf", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "1968", "original-title": [], "page": "9202", "prefix": "10.3390", "published": { "date-parts": [ [ 2023, 5, 24 ] ] }, "published-online": { "date-parts": [ [ 2023, 5, 24 ] ] }, "publisher": "MDPI AG", "reference": [ { "DOI": "10.1186/s13054-020-03120-0", "article-title": "Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19", "author": "Ni", "doi-asserted-by": "crossref", "first-page": "422", "journal-title": "Crit. 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