{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T05:20:09Z","timestamp":1764652809302,"version":"3.46.0"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T00:00:00Z","timestamp":1764374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Foundation of China","doi-asserted-by":"crossref","award":["82204681"],"award-info":[{"award-number":["82204681"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003785","name":"Medical Scientific Research Foundation of Guangdong Province of China","doi-asserted-by":"crossref","award":["A2024128"],"award-info":[{"award-number":["A2024128"]}],"id":[{"id":"10.13039\/501100003785","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>SARS-CoV-2 virus contains two highly conserved domains, the papain-like protease (PLpro) and main protease (Mpro), which play important roles in virus replication, immune suppression, and the induction of inflammation in host tissue. In this study, we applied small-molecule chip screening, enzymatic assays, SARS-CoV-2 spike pseudotyped virus detection and molecular docking to find potential Mpro or PLpro inhibitors. Two small molecules, oxytocin and risedronate sodium, stood out in drug repurposing. Oxytocin and risedronate sodium were shown to influence the activities of Mpro and PLpro, thereby preventing the virus from replication, which may alleviate SARS-CoV-2 infection. Thus, oxytocin, risedronate sodium, and cephalosporins may expand the drug library for treating coronavirus infection.<\/jats:p>","DOI":"10.3390\/v17121564","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T13:03:02Z","timestamp":1764594182000},"page":"1564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting SARS-CoV-2 Mpro and PLpro by Repurposing Clinically Approved Drugs"],"prefix":"10.3390","volume":"17","author":[{"given":"Qiaoyu","family":"Fang","sequence":"first","affiliation":[{"name":"Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen 518020, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8804-0563","authenticated-orcid":false,"given":"Meng","family":"Lu","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen 518020, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derong","family":"Chen","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen 518020, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0609-5333","authenticated-orcid":false,"given":"Liangxu","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213000, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0260-1099","authenticated-orcid":false,"given":"Wenxu","family":"Hong","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen 518020, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen 518020, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5047-1730","authenticated-orcid":false,"given":"Xuqiao","family":"Hu","sequence":"additional","affiliation":[{"name":"Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen 518020, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1002\/prot.26250","article-title":"Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first 6 months of the COVID-19 pandemic","volume":"90","author":"Lubin","year":"2022","journal-title":"Proteins"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41579-020-00459-7","article-title":"Characteristics of SARS-CoV-2 and COVID-19","volume":"19","author":"Hu","year":"2021","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41586-020-2223-y","article-title":"Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors","volume":"582","author":"Jin","year":"2020","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.jmb.2005.09.012","article-title":"pH-dependent conformational flexibility of the SARS-CoV main proteinase (M(pro)) dimer: Molecular dynamics simulations and multiple X-ray structure analyses","volume":"354","author":"Tan","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41586-020-2601-5","article-title":"Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity","volume":"587","author":"Shin","year":"2020","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7561","DOI":"10.1021\/acs.jmedchem.2c00303","article-title":"Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease","volume":"65","author":"Tan","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eabd4596","DOI":"10.1126\/sciadv.abd4596","article-title":"Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti-COVID-19 drug design","volume":"6","author":"Rut","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1126\/science.adm9724","article-title":"Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model","volume":"383","author":"Tan","year":"2024","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e2404884","DOI":"10.1002\/advs.202404884","article-title":"Miniaturized Modular Click Chemistry-enabled Rapid Discovery of Unique SARS-CoV-2 Mpro Inhibitors with Robust Potency and Drug-like Profile","volume":"11","author":"Yang","year":"2024","journal-title":"Adv. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eadi0979","DOI":"10.1126\/scitranslmed.adi0979","article-title":"An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations","volume":"16","author":"Westberg","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/s41564-024-01618-9","article-title":"Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir","volume":"9","author":"Chen","year":"2024","journal-title":"Nat. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1039\/D0CC06870E","article-title":"Mass spectrometry reveals potential of beta-lactams as SARS-CoV-2 M(pro) inhibitors","volume":"57","author":"Malla","year":"2021","journal-title":"Chem. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102269","DOI":"10.1101\/pdb.prot102269","article-title":"Bradford Assay for Determining Protein Concentration","volume":"2020","author":"Kielkopf","year":"2020","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s10544-011-9546-2","article-title":"Novel disposable biochip platform employing supercritical angle fluorescence for enhanced fluorescence collection","volume":"13","author":"Hill","year":"2011","journal-title":"Biomed. Microdevices"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/s41586-019-1722-1","article-title":"Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds","volume":"575","author":"Li","year":"2019","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1007\/978-1-4939-6584-7_11","article-title":"Discovery of RNA Binding Small Molecules Using Small Molecule Microarrays","volume":"1518","author":"Connelly","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2344","DOI":"10.1038\/nprot.2006.282","article-title":"A method for the covalent capture and screening of diverse small molecules in a microarray format","volume":"1","author":"Bradner","year":"2006","journal-title":"Nat. Protoc."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhu, C., Zhu, X., Landry, J.P., Cui, Z., Li, Q., Dang, Y., Mi, L., Zheng, F., and Fei, Y. (2016). Developing an Efficient and General Strategy for Immobilization of Small Molecules onto Microarrays Using Isocyanate Chemistry. Sensors, 16.","DOI":"10.3390\/s16030378"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1080\/14756366.2022.2132486","article-title":"Ligand-based discovery of coronavirus main protease inhibitors using MACAW molecular embeddings","volume":"38","author":"Dong","year":"2023","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bittrich, S., Bhikadiya, C., Bi, C., Chao, H., Duarte, J.M., Dutta, S., Fayazi, M., Henry, J., Khokhriakov, I., and Lowe, R. (2023). RCSB Protein Data Bank: Efficient Searching and Simultaneous Access to One Million Computed Structure Models Alongside the PDB Structures Enabled by Architectural Advances. J. Mol. Biol., 435.","DOI":"10.1016\/j.jmb.2023.167994"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kim, S., Cheng, T., He, S., Thiessen, P.A., Li, Q., Gindulyte, A., and Bolton, E.E. (2022). PubChem Protein, Gene, Pathway, and Taxonomy Data Collections: Bridging Biology and Chemistry through Target-Centric Views of PubChem Data. J. Mol. Biol., 434.","DOI":"10.1016\/j.jmb.2022.167514"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/jcc.20634","article-title":"A semiempirical free energy force field with charge-based desolvation","volume":"28","author":"Huey","year":"2007","journal-title":"J. Comput. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/jssc.202100570","article-title":"Investigating interactions between chloroquine\/hydroxychloroquine and their single enantiomers and angiotensin-converting enzyme 2 by a cell membrane chromatography method","volume":"45","author":"Jia","year":"2022","journal-title":"J. Sep. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"153333","DOI":"10.1016\/j.phymed.2020.153333","article-title":"Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus","volume":"79","author":"Wang","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Roy, U. (2023). Computational Investigation of Selected Spike Protein Mutations in SARS-CoV-2: Delta, Omicron, and Some Circulating Subvariants. Pathogens, 13.","DOI":"10.3390\/pathogens13010010"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1002\/cbin.12130","article-title":"What makes SARS-CoV-2 unique? Focusing on the spike protein","volume":"48","author":"Qian","year":"2024","journal-title":"Cell Biol. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1007\/s12551-023-01153-7","article-title":"SARS-CoV-2 proteins structural studies using synchrotron radiation","volume":"15","author":"Kosenko","year":"2023","journal-title":"Biophys. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1021\/acsinfecdis.3c00418","article-title":"Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication","volume":"10","author":"Zhou","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Meng, Q.T., Song, W.Q., Churilov, L.P., Zhang, F.M., and Wang, Y.F. (2023). Psychophysical therapy and underlying neuroendocrine mechanisms for the rehabilitation of long COVID-19. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1120475"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wang, S.C., Zhang, F., Zhu, H., Yang, H., Liu, Y., Wang, P., Parpura, V., and Wang, Y.F. (2022). Potential of Endogenous Oxytocin in Endocrine Treatment and Prevention of COVID-19. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.799521"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Tsegay, K.B., Adeyemi, C.M., Gniffke, E.P., Sather, D.N., Walker, J.K., and Smith, S.E.P. (2021). A Repurposed Drug Screen Identifies Compounds That Inhibit the Binding of the COVID-19 Spike Protein to ACE2. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.685308"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"110329","DOI":"10.1016\/j.mehy.2020.110329","article-title":"Hypothesis: Oxytocin is a direct COVID-19 antiviral","volume":"145","author":"Diep","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.2174\/22123873MTA5pODYpw","article-title":"Oxytocin as a Potential Adjuvant Against COVID-19 Infection","volume":"21","author":"Thakur","year":"2021","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109785","DOI":"10.1016\/j.mehy.2020.109785","article-title":"Oxytocin as a potential defence against COVID-19?","volume":"140","author":"Soumier","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1515\/hmbci-2021-0034","article-title":"Oxytocin, the panacea for long-COVID? A review","volume":"43","author":"Diep","year":"2022","journal-title":"Horm. Mol. Biol. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"105601","DOI":"10.1016\/j.psyneuen.2021.105601","article-title":"Consequences of pandemic-associated social restrictions: Role of social support and the oxytocin system","volume":"135","author":"Gryksa","year":"2022","journal-title":"Psychoneuroendocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"119130","DOI":"10.1016\/j.lfs.2021.119130","article-title":"Cardiovascular protective properties of oxytocin against COVID-19","volume":"270","author":"Wang","year":"2021","journal-title":"Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1080\/15622975.2020.1814408","article-title":"Can intravenous oxytocin infusion counteract hyperinflammation in COVID-19 infected patients?","volume":"22","author":"Buemann","year":"2021","journal-title":"World J. Biol. Psychiatry Off. J. World Fed. Soc. Biol. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.jconrel.2023.11.025","article-title":"Micronanoparticled risedronate exhibits potent vaccine adjuvant effects","volume":"365","author":"Nie","year":"2024","journal-title":"J. Control Release"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.jconrel.2024.01.033","article-title":"Risedronate-functionalized manganese-hydroxyapatite amorphous particles: A potent adjuvant for subunit vaccines and cancer immunotherapy","volume":"367","author":"Zhang","year":"2024","journal-title":"J. Control Release"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1002\/jbmr.4419","article-title":"The Use of Oral Amino-Bisphosphonates and Coronavirus Disease 2019 (COVID-19) Outcomes","volume":"36","author":"Perrone","year":"2021","journal-title":"J. Bone Min. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1021\/acs.jcim.3c00282","article-title":"Targeting SARS-CoV-2 Main Protease: A Successful Story Guided by an In Silico Drug Repurposing Approach","volume":"63","author":"Ambrosio","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e06387","DOI":"10.1016\/j.heliyon.2021.e06387","article-title":"The study of antiviral drugs targeting SARS-CoV-2 nucleocapsid and spike proteins through large-scale compound repurposing","volume":"7","author":"Hu","year":"2021","journal-title":"Heliyon"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bagdonas, M., Cerepenkaite, K., Mickeviciute, A., Kananaviciute, R., Grybaite, B., Anusevicius, K., Ruksenaite, A., Kojis, T., Gedgaudas, M., and Mickevicius, V. (2023). Screening, Synthesis and Biochemical Characterization of SARS-CoV-2 Protease Inhibitors. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713491"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1007\/s11224-022-02036-5","article-title":"In silico studies of M(pro) and PL(pro) from SARS-CoV-2 and a new class of cephalosporin drugs containing 1,2,4-thiadiazole","volume":"33","author":"Delgado","year":"2022","journal-title":"Struct. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"198915","DOI":"10.1016\/j.virusres.2022.198915","article-title":"Identification of hACE2-interacting sites in SARS-CoV-2 spike receptor binding domain for antiviral drugs screening","volume":"321","author":"Hu","year":"2022","journal-title":"Virus Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6921","DOI":"10.1080\/07391102.2021.1891969","article-title":"Structure-based virtual screening, molecular dynamics and binding affinity calculations of some potential phytocompounds against SARS-CoV-2","volume":"40","author":"Naik","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/0014-5793(84)81326-5","article-title":"The effect of lipopolysaccharide on lipid bilayer permeability of beta-lactam antibiotics","volume":"170","author":"Hiruma","year":"1984","journal-title":"FEBS Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1152\/physrev.00031.2017","article-title":"The Oxytocin Receptor: From Intracellular Signaling to Behavior","volume":"98","author":"Jurek","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3183","DOI":"10.7150\/thno.52570","article-title":"Engineering exosomes for targeted drug delivery","volume":"11","author":"Liang","year":"2021","journal-title":"Theranostics"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/12\/1564\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T05:16:24Z","timestamp":1764652584000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/12\/1564"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,29]]},"references-count":50,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["v17121564"],"URL":"https:\/\/doi.org\/10.3390\/v17121564","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2025,11,29]]}}}