{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:43:47Z","timestamp":1790189027165,"version":"4.1.0"},"reference-count":105,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020595","name":"National Science and Technology Council of Taiwan","doi-asserted-by":"crossref","award":["(MOST 111-2321-B-255-001), MOST 111-2320-B-038-040-MY3)"],"award-info":[{"award-number":["(MOST 111-2321-B-255-001), MOST 111-2320-B-038-040-MY3)"]}],"id":[{"id":"10.13039\/100020595","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004391","name":"China Medical University Hospital","doi-asserted-by":"publisher","award":["CMU110-MF-52"],"award-info":[{"award-number":["CMU110-MF-52"]}],"id":[{"id":"10.13039\/501100004391","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>This study identifies the secondary metabolites from <jats:italic>Alternaria alternate<\/jats:italic> and evaluates their ACE-2: Spike RBD (SARS-CoV-2) inhibitory activity confirmed <jats:italic>via<\/jats:italic> immunoblotting in human lung microvascular endothelial cells. In addition, their <jats:italic>in vitro<\/jats:italic> anti-inflammatory potential was assessed using a cell-based assay in LPS-treated RAW 264.7 macrophage cells. Two novel compounds, altenuline (<jats:bold>1<\/jats:bold>), phthalic acid bis (7\u2019\/7\u2019\u2019 pentyloxy) isohexyl ester (<jats:bold>2<\/jats:bold>), along with 1-deoxyrubralactone (<jats:bold>3<\/jats:bold>) alternariol-5-<jats:italic>O<\/jats:italic>-methyl ether (<jats:bold>4<\/jats:bold>) and alternariol (<jats:bold>5<\/jats:bold>) were identified. Molecular docking and <jats:italic>in vitro<\/jats:italic> studies showed that compounds <jats:bold>2<\/jats:bold> and <jats:bold>4<\/jats:bold> were promising to counteract SARS-CoV-2 attachment to human ACE-2. Thus, they are considered promising natural anti-viral agents. SwissADME in silico analysis was conducted to predict the drug-like potential. Immunoblotting analysis confirmed that the tested compounds (<jats:bold>1\u20134<\/jats:bold>) demonstrated downregulation of ACE-2 expression in the endothelial cells from the lungs with variable degrees. Furthermore, the tested compounds (<jats:bold>1\u20134<\/jats:bold>) showed promising anti-inflammatory activities through TNF-\u03b1: TNFR2 inhibitory activity and their inhibitory effect on the proinflammatory cytokines (TNF-\u03b1 and IL-6) in LPS-stimulated monocytes. In conclusion, our study, for the first time, provides beneficial experimental confirmation for the efficiency of the <jats:italic>A<\/jats:italic>. <jats:italic>alternate<\/jats:italic> secondary metabolites for the treatment of COVID-19 as they hinder SARS-CoV-2 infection and lower inflammatory responses initiated by SARS-CoV-2. <jats:italic>A<\/jats:italic>. <jats:italic>alternate<\/jats:italic> and its metabolites are considered in developing preventative and therapeutic tactics for COVID-19.<\/jats:p>","DOI":"10.1371\/journal.pone.0313616","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T18:58:12Z","timestamp":1737745092000},"page":"e0313616","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Secondary metabolites of Alternaria alternate appraisal of their SARS-CoV-2 inhibitory and anti-inflammatory potentials"],"prefix":"10.1371","volume":"20","author":[{"given":"Fatma A.","family":"Moharram","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reham R.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahenda","family":"Mahgoub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Abdel-Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed 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