{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T17:40:25Z","timestamp":1773337225301,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:00:00Z","timestamp":1773273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    This study aimed to identify small molecules that inhibit the binding of the SARS-CoV-2 Spike protein to its host receptor, angiotensin-converting enzyme 2 (ACE2), without impairing the enzymatic activity of ACE2. Such inhibitors may support the development of broad-spectrum antivirals and therapeutic strategies for emerging SARS-CoV-2 variants. Through extensive screening using both cell-free and cell-based assays, we identified phenoxy-methylaniline (PoMA) compounds as effective inhibitors of the SARS-CoV-2 Spike-ACE2 interaction. Among these, PoMA-10, featuring trifluoromethoxy and dimethylaniline moieties, exhibited the most potent inhibitory activity while preserving ACE2 enzymatic function. Computational modeling predicted direct binding of PoMA-10 to ACE2, which was corroborated by protein mobility shift assays. This was further substantiated by surface plasmon resonance analysis and molecular dynamics simulations, which confirmed the stable binding of PoMA-10\u00a0at an interface-adjacent site on ACE2 and the disruption of SARS-CoV-2 Spike\u2013ACE2 interaction. In Vero cells, PoMA-10 significantly reduced infection by ancestral SARS-CoV-2 and the Delta and Gamma variants. Moreover, PoMA-10 alleviated lung epithelial cell damage and protected against lipopolysaccharide-induced lung injury\n                    <jats:italic>in vivo<\/jats:italic>\n                    . These findings demonstrate that PoMA-10 functions as a dual-action inhibitor blocking viral entry and protecting against lung injury, and highlight its potential as a therapeutic candidate in the management of COVID-19 and related pulmonary complications.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1755268","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T06:48:30Z","timestamp":1773298110000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["PoMA-10: a dual-action antiviral disrupting SARS-CoV-2 Spike\u2013ACE2 interaction and protecting lung tissue"],"prefix":"10.3389","volume":"17","author":[{"given":"Soheun","family":"Lee","sequence":"first","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suh Jin","family":"Yoon","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]},{"name":"Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihae","family":"Lim","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji Hyun","family":"Oh","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae-Sang","family":"Ryu","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gahee","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunwoo","family":"Kang","sequence":"additional","affiliation":[{"name":"HITS Inc.","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nayoon","family":"Jo","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]},{"name":"Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sehan","family":"Lee","sequence":"additional","affiliation":[{"name":"HITS Inc.","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunbok","family":"Jang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]},{"name":"Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoonji","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Chung-Ang University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunjeong","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun Sook","family":"Hwang","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University","place":["Seoul, Republic of Korea"]},{"name":"Gradutate Program in Innovative Biomaterials Convergence, Ewha Womans University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1038\/s41591-020-0820-9","article-title":"The proximal origin of SARS-CoV-2","volume":"26","author":"Andersen","year":"2020","journal-title":"Nat. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.3390\/biom13101452","article-title":"Insights into COVID-19: perspectives on drug remedies and host cell responses","volume":"13","author":"Awad","year":"2023","journal-title":"Biomolecules"},{"key":"B3","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s40268-020-00312-5","article-title":"Identification of a potential peptide inhibitor of SARS-CoV-2 targeting its entry into the host cells","volume":"20","author":"Baig","year":"2020","journal-title":"Drugs R. D."},{"key":"B4","doi-asserted-by":"publisher","first-page":"38","DOI":"10.3390\/biomedicines10010038","article-title":"Vascular effects of low-dose ACE2 inhibitor MLN-4760-Benefit or detriment in essential hypertension?","volume":"10","author":"Berenyiova","year":"2021","journal-title":"Biomedicines"},{"key":"B5","doi-asserted-by":"publisher","first-page":"e0242128","DOI":"10.1371\/journal.pone.0242128","article-title":"Reproductive number of coronavirus: a systematic review and meta-analysis based on global level evidence","volume":"15","author":"Billah","year":"2020","journal-title":"PLoS One"},{"key":"B6","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1248\/cpb.55.304","article-title":"New diphenyl ethers from the insect pathogenic fungus cordyceps sp. BCC 1861","volume":"55","author":"Bunyapaiboonsri","year":"2007","journal-title":"Chem. Pharm. Bull. (Tokyo)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1021\/jf00083a037","article-title":"Some novel diphenyl ether herbicides with peroxidizing activity","volume":"36","author":"Camilleri","year":"1988","journal-title":"J. Agric. Food Chem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1002\/jmv.27580","article-title":"Distinct mutations and lineages of SARS-CoV-2 virus in the early phase of COVID-19 pandemic and subsequent 1-year global expansion","volume":"94","author":"Chen","year":"2022","journal-title":"J. Med. Virol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s12985-021-01624-x","article-title":"Keep out! SARS-CoV-2 entry inhibitors: their role and utility as COVID-19 therapeutics","volume":"18","author":"Chitsike","year":"2021","journal-title":"Virol. J."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1016\/j.str.2024.08.005","article-title":"Structural review of SARS-CoV-2 antiviral targets","volume":"32","author":"Cui","year":"2024","journal-title":"Structure"},{"key":"B11","doi-asserted-by":"publisher","first-page":"100144","DOI":"10.1016\/j.cellin.2023.100144","article-title":"Development of SARS-CoV-2 entry antivirals","volume":"3","author":"Dong","year":"2024","journal-title":"Cell Insight"},{"key":"B12","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1021\/acsptsci.2c00003","article-title":"Allosteric site of ACE-2 as a drug target for COVID-19","volume":"5","author":"Dutta","year":"2022","journal-title":"ACS Pharmacol. Transl. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"633","DOI":"10.24272\/j.issn.2095-8137.2021.206","article-title":"Captopril alleviates lung inflammation in SARS-CoV-2-infected hypertensive mice","volume":"42","author":"Gao","year":"2021","journal-title":"Zool. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.jfluchem.2018.11.002","article-title":"Recent progress in the strategic incorporation of fluorine into medicinally active compounds","volume":"217","author":"Haranahalli","year":"2019","journal-title":"J. Fluor Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"103255","DOI":"10.1016\/j.ebiom.2021.103255","article-title":"Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity","volume":"65","author":"Hoffmann","year":"2021","journal-title":"eBioMedicine"},{"key":"B16","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor","volume":"181","author":"Hoffmann","year":"","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/s41586-020-2575-3","article-title":"Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2","volume":"585","author":"Hoffmann","year":"","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00754-20","article-title":"Nafamostat mesylate blocks activation of SARS-CoV-2: new treatment option for COVID-19","volume":"64","author":"Hoffmann","year":"","journal-title":"Antimicrob. Agents Chemother."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1021\/acscentsci.3c00538","article-title":"Naturally occurring mutations of SARS-CoV-2 main protease confer drug resistance to nirmatrelvir","volume":"9","author":"Hu","year":"2023","journal-title":"ACS Cent. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1038\/s41586-022-05514-2","article-title":"Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir","volume":"613","author":"Iketani","year":"2023","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e00819","DOI":"10.1128\/AAC.00819-20","article-title":"Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs","volume":"64","author":"Jeon","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e0281522","DOI":"10.1128\/mbio.02815-22","article-title":"The substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitor in vitro and confer resistance to nirmatrelvir","volume":"14","author":"Jochmans","year":"2023","journal-title":"mBio"},{"key":"B24","doi-asserted-by":"publisher","first-page":"4231","DOI":"10.1038\/s41467-023-40018-1","article-title":"In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir","volume":"14","author":"Kiso","year":"2023","journal-title":"Nat. Commun."},{"key":"B25","doi-asserted-by":"publisher","first-page":"103579","DOI":"10.1016\/j.drudis.2023.103579","article-title":"COVID-19 therapeutics: small-Molecule drug development targeting SARS-CoV-2 main protease","volume":"28","author":"Kronenberger","year":"2023","journal-title":"Drug Discov. Today"},{"key":"B26","doi-asserted-by":"publisher","first-page":"116674","DOI":"10.1016\/j.biopha.2024.116674","article-title":"MPoMA protects against lung epithelial cell injury via p65 degradation","volume":"175","author":"Lee","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"B27","doi-asserted-by":"publisher","first-page":"109978","DOI":"10.1016\/j.jfluchem.2022.109978","article-title":"Successful trifluoromethoxy-containing pharmaceuticals and agrochemicals","volume":"257","author":"Liu","year":"2022","journal-title":"J. Fluor. Chem."},{"key":"B28","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.3390\/molecules27072070","article-title":"Structure\/function analysis of truncated amino-terminal ACE2 peptide analogs that bind to SARS-CoV-2 spike glycoprotein","volume":"27","author":"Mackin","year":"2022","journal-title":"Molecules"},{"key":"B29","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1038\/s41591-021-01282-0","article-title":"Developing therapeutic approaches for twenty-first-century emerging infectious viral diseases","volume":"27","author":"Meganck","year":"2021","journal-title":"Nat. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"eade8778","DOI":"10.1126\/sciadv.ade8778","article-title":"Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors","volume":"9","author":"Moghadasi","year":"2023","journal-title":"Sci. Adv."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2054","DOI":"10.3390\/pr10102054","article-title":"FDA-approved trifluoromethyl group-containing drugs: a review of 20 years","volume":"10","author":"Nair","year":"2022","journal-title":"Processes"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1705","DOI":"10.1097\/HJH.0000000000002829","article-title":"The interaction of the severe acute respiratory syndrome coronavirus 2 spike protein with drug-inhibited angiotensin converting enzyme 2 studied by molecular dynamics simulation","volume":"39","author":"Nami","year":"2021","journal-title":"J. Hypertens."},{"key":"B33","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1038\/s41431-023-01462-1","article-title":"A comprehensive SARS-CoV-2 and COVID-19 review, part 2: host extracellular to systemic effects of SARS-CoV-2 infection","volume":"32","author":"Narayanan","year":"2024","journal-title":"Eur. J. Hum. Genet."},{"key":"B34","doi-asserted-by":"publisher","first-page":"6827","DOI":"10.1016\/j.bmc.2015.10.003","article-title":"Synthesis of stereochemically diverse cyclic analogs of tubulysins","volume":"23","author":"Park","year":"2015","journal-title":"Bioorg Med. Chem."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01031-17","article-title":"Complexities of viral mutation rates","volume":"92","author":"Peck","year":"2018","journal-title":"J. Virol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"834098","DOI":"10.3389\/fimmu.2022.834098","article-title":"SARS-CoV-2's variants of concern: a brief characterization","volume":"13","author":"Scovino","year":"2022","journal-title":"Front. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/s41586-022-04661-w","article-title":"A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic","volume":"605","author":"Shapira","year":"2022","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1016\/j.cell.2020.03.045","article-title":"Structural and functional basis of SARS-CoV-2 entry by using human ACE2","volume":"181","author":"Wang","year":"2020","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/s41401-021-00735-z","article-title":"Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein","volume":"43","author":"Wang","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"B40","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1007\/s00259-024-06831-6","article-title":"Development of radiofluorinated MLN-4760 derivatives for PET imaging of the SARS-CoV-2 entry receptor ACE2","volume":"52","author":"Wang","year":"2024","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"B41","doi-asserted-by":"publisher","first-page":"115503","DOI":"10.1016\/j.ejmech.2023.115503","article-title":"Bench-to-bedside: innovation of small molecule anti-SARS-CoV-2 drugs in China","volume":"257","author":"Yang","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"e1009195","DOI":"10.1371\/journal.ppat.1009195","article-title":"K18-hACE2 mice develop respiratory disease resembling severe COVID-19","volume":"17","author":"Yinda","year":"2021","journal-title":"PLoS Pathog."},{"key":"B43","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/s41586-020-2943-z","article-title":"COVID-19 treatments and pathogenesis including anosmia in K18-hACE2 mice","volume":"589","author":"Zheng","year":"2021","journal-title":"Nature"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1755268\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T06:48:31Z","timestamp":1773298111000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1755268\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,12]]},"references-count":43,"alternative-id":["10.3389\/fphar.2026.1755268"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1755268","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,12]]},"article-number":"1755268"}}