Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant metabolites

{ 'indexed': {'date-parts': [[2023, 4, 4]], 'date-time': '2023-04-04T05:31:46Z', 'timestamp': 1680586306786}, 'reference-count': 94, 'publisher': 'Springer Science and Business Media LLC', 'issue': '1', 'license': [ { 'start': { 'date-parts': [[2023, 4, 1]], 'date-time': '2023-04-01T00:00:00Z', 'timestamp': 1680307200000}, 'content-version': 'tdm', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}, { 'start': { 'date-parts': [[2023, 4, 1]], 'date-time': '2023-04-01T00:00:00Z', 'timestamp': 1680307200000}, 'content-version': 'vor', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0'}], 'funder': [ { 'DOI': '10.13039/501100003009', 'name': 'Science and Technology Development Fund', 'doi-asserted-by': 'publisher', 'award': ['45420']}, { 'DOI': '10.13039/501100007637', 'name': 'German University in Cairo', 'doi-asserted-by': 'crossref'}], 'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False}, 'abstract': '<jats:title>Abstract</jats:title><jats:p>SARS-CoV-2 has been responsible for the major ' 'worldwide pandemic of COVID-19. Despite the enormous success of vaccination campaigns, virus ' 'infections are still prevalent and effective antiviral therapies are urgently needed. ' 'Viroporins are essential for virus replication and release, and are thus promising ' 'therapeutic targets. Here, we studied the expression and function of recombinant ORF3a ' 'viroporin of SARS-CoV-2 using a combination of cell viability assays and patch-clamp ' 'electrophysiology. ORF3a was expressed in HEK293 cells and transport to the plasma membrane ' 'verified by a dot blot assay. Incorporation of a membrane-directing signal peptide increased ' 'plasma membrane expression. Cell viability tests were carried out to measure cell damage ' 'associated with ORF3a activity, and voltage-clamp\xa0recordings verified its channel ' 'activity. The classical viroporin inhibitors amantadine and rimantadine inhibited ORF3a ' 'channels. A series of ten flavonoids and polyphenolics were studied. Kaempferol, quercetin, ' 'epigallocatechin gallate, nobiletin, resveratrol and curcumin were ORF3a inhibitors, with ' 'IC<jats:sub>50</jats:sub> values ranging between 1 and 6\xa0µM, while 6-gingerol, apigenin, ' 'naringenin and genistein were inactive. For flavonoids, inhibitory activity could be related ' 'to the pattern of OH groups on the chromone ring system. Thus, the ORF3a viroporin of ' 'SARS-CoV-2 may indeed be a promising target for antiviral drugs.</jats:p>', 'DOI': '10.1038/s41598-023-31764-9', 'type': 'journal-article', 'created': {'date-parts': [[2023, 4, 3]], 'date-time': '2023-04-03T05:50:55Z', 'timestamp': 1680501055000}, 'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Channel activity of SARS-CoV-2 viroporin ORF3a inhibited by adamantanes and phenolic plant ' 'metabolites', 'prefix': '10.1038', 'volume': '13', 'author': [ {'given': 'Marina Sherif', 'family': 'Fam', 'sequence': 'first', 'affiliation': []}, {'given': 'Christine Adel', 'family': 'Sedky', 'sequence': 'additional', 'affiliation': []}, {'given': 'Nancy Osama', 'family': 'Turky', 'sequence': 'additional', 'affiliation': []}, {'given': 'Hans-Georg', 'family': 'Breitinger', 'sequence': 'additional', 'affiliation': []}, {'given': 'Ulrike', 'family': 'Breitinger', 'sequence': 'additional', 'affiliation': []}], 'member': '297', 'published-online': {'date-parts': [[2023, 4, 1]]}, 'reference': [ { 'issue': '4', 'key': '31764_CR1', 'doi-asserted-by': 'publisher', 'first-page': '536', 'DOI': '10.1038/s41564-020-0695-z', 'volume': '5', 'author': 'AE Gorbalenya', 'year': '2020', 'unstructured': 'Gorbalenya, A. 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