{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T23:45:24Z","timestamp":1790379924328,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T00:00:00Z","timestamp":1610496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005362","name":"Universita degli Studi di Bari Aldo Moro","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100005362","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2.<\/jats:p>","DOI":"10.3390\/v13010106","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T21:50:54Z","timestamp":1610574654000},"page":"106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Systematic Search for SARS-CoV-2 Main Protease Inhibitors for Drug Repurposing: Ethacrynic Acid as a Potential Drug"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9981-4121","authenticated-orcid":false,"given":"Camilla","family":"Isgr\u00f2","sequence":"first","affiliation":[{"name":"Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Piazza G. Cesare 11, 70124 Bari, Italy"},{"name":"Department of Medicine, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8535-7601","authenticated-orcid":false,"given":"Anna Maria","family":"Sardanelli","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Piazza G. Cesare 11, 70124 Bari, Italy"},{"name":"Department of Medicine, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3447-1535","authenticated-orcid":false,"given":"Luigi Leonardo","family":"Palese","sequence":"additional","affiliation":[{"name":"Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Piazza G. Cesare 11, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/S0140-6736(20)30185-9","article-title":"A novel coronavirus outbreak of global health concern","volume":"395","author":"Wang","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/s41564-020-0695-z","article-title":"The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2","volume":"5","author":"Gorbalenya","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0065-3527(08)60286-9","article-title":"The molecular biology of coronaviruses","volume":"Volume 48","author":"Lai","year":"1997","journal-title":"Advances in Virus Research"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and evolution of pathogenic coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4085","DOI":"10.1111\/febs.12936","article-title":"From SARS to MERS: Crystallographic studies on coronaviral proteases enable antiviral drug design","volume":"281","author":"Hilgenfeld","year":"2014","journal-title":"FEBS J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1093\/emboj\/cdf327","article-title":"Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra \u03b1-helical domain","volume":"21","author":"Anand","year":"2002","journal-title":"EMBO J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1126\/science.1085658","article-title":"Coronavirus main proteinase (3CLpro) structure: Basis for design of anti-SARS drugs","volume":"300","author":"Anand","year":"2003","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"22677","DOI":"10.1038\/srep22677","article-title":"Structure of main protease from human coronavirus NL63: Insights for wide spectrum anti-coronavirus drug design","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8647","DOI":"10.1128\/JVI.00298-08","article-title":"Structure of the main protease from a global infectious human coronavirus, HCoV-HKU1","volume":"82","author":"Zhao","year":"2008","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5717","DOI":"10.1073\/pnas.0510851103","article-title":"Severe acute respiratory syndrome coronavirus papain-like protease: Structure of a viral deubiquitinating enzyme","volume":"103","author":"Ratia","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., and Peng, C. (2020). Structure of M pro from SARS-CoV-2 and discovery of its inhibitors. Nature, 1\u20135.","DOI":"10.1038\/s41586-020-2223-y"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Palese, L.L. (2020). The structural landscape of SARS-CoV-2 main protease: Hints for inhibitor search. ChemRxiv.","DOI":"10.26434\/chemrxiv.12209744"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kapusta, K., Kar, S., Collins, J.T., Franklin, L.M., Kolodziejczyk, W., Leszczynski, J., and Hill, G.A. (2020). Protein reliability analysis and virtual screening of natural inhibitors for SARS-CoV-2 main protease (Mpro) through docking, molecular mechanic & dynamic, and ADMET profiling. J. Biomol. Struct. Dyn., 1\u201318.","DOI":"10.1080\/07391102.2020.1806930"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ojha, P.K., Kar, S., Krishna, J.G., Roy, K., and Leszczynski, J. (2020). Therapeutics for COVID-19: From computation to practices\u2014Where we are, where we are heading to. Mol. Divers., 1\u201335.","DOI":"10.1007\/s11030-020-10134-x"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gimeno, A., Mestres-Truyol, J., Ojeda-Montes, M.J., Macip, G., Saldivar-Espinoza, B., Cereto-Massagu\u00e9, A., Pujadas, G., and Garcia-Vallv\u00e9, S. (2020). Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113793"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13765-020-00564-4","article-title":"Screening marine algae metabolites as high-affinity inhibitors of SARS-CoV-2 main protease (3CLpro): An in silico analysis to identify novel drug candidates to combat COVID-19 pandemic","volume":"63","author":"Muteeb","year":"2020","journal-title":"Appl. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/d41573-020-00016-0","article-title":"Therapeutic options for the 2019 novel coronavirus (2019-nCoV)","volume":"19","author":"Li","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Low, Z.Y., Farouk, I.A., and Lal, S.K. (2020). Drug repositioning: New approaches and future prospects for life-debilitating diseases and the COVID-19 pandemic outbreak. Viruses, 12.","DOI":"10.3390\/v12091058"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Martorana, A., Gentile, C., and Lauria, A. (2020). In Silico Insights into the SARS CoV-2 Main Protease Suggest NADH Endogenous Defences in the Control of the Pandemic Coronavirus Infection. Viruses, 12.","DOI":"10.3390\/v12080805"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kumar, S., Zhi, K., Mukherji, A., and Gerth, K. (2020). Repurposing antiviral protease inhibitors using extracellular vesicles for potential therapy of COVID-19. Viruses, 12.","DOI":"10.3390\/v12050486"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.bbapap.2017.08.009","article-title":"Conformations of the HIV-1 protease: A crystal structure data set analysis","volume":"1865","author":"Palese","year":"2017","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.dib.2017.09.076","article-title":"Analysis of the conformations of the HIV-1 protease from a large crystallographic data set","volume":"15","author":"Palese","year":"2017","journal-title":"Data Brief"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Gnoni, A., De Nitto, E., Scacco, S., Santacroce, L., and Palese, L.L. (2019). A New Look at the Structures of Old Sepsis Actors by Exploratory Data Analysis Tools. Antibiotics, 8.","DOI":"10.3390\/antibiotics8040225"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.jmb.2006.11.073","article-title":"Production of authentic SARS-CoV Mpro with enhanced activity: Application as a novel tag-cleavage endopeptidase for protein overproduction","volume":"366","author":"Xue","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4971","DOI":"10.1021\/jm0603926","article-title":"Synthesis, Crystal Structure, Structure- Activity Relationships, and Antiviral Activity of a Potent SARS Coronavirus 3CL Protease Inhibitor","volume":"49","author":"Yang","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.antiviral.2011.08.001","article-title":"Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease","volume":"92","author":"Zhu","year":"2011","journal-title":"Antiviral Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm301580n","article-title":"Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease","volume":"56","author":"Jacobs","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.jmb.2007.06.001","article-title":"A mechanistic view of enzyme inhibition and peptide hydrolysis in the active site of the SARS-CoV 3C-like peptidase","volume":"371","author":"Yin","year":"2007","journal-title":"J. Mol. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.chembiol.2008.04.011","article-title":"A structural view of the inactivation of the SARS coronavirus main proteinase by benzotriazole esters","volume":"15","author":"Verschueren","year":"2008","journal-title":"Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5454","DOI":"10.1016\/j.febslet.2007.10.048","article-title":"Structural basis of mercury-and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors","volume":"581","author":"Lee","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7646","DOI":"10.1074\/jbc.M807947200","article-title":"Structural basis of inhibition specificities of 3C and 3C-like proteases by zinc-coordinating and peptidomimetic compounds","volume":"284","author":"Lee","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5154","DOI":"10.1021\/jm060207o","article-title":"Structure-based drug design and structural biology study of novel nonpeptide inhibitors of severe acute respiratory syndrome coronavirus main protease","volume":"49","author":"Lu","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"12997","DOI":"10.1073\/pnas.1601327113","article-title":"SARS-CoV 3CL protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity","volume":"113","author":"Muramatsu","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/j.jmb.2005.09.004","article-title":"Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-like aza-peptide epoxide","volume":"353","author":"Lee","year":"2005","journal-title":"J. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Fearon, D., Owen, C., Douangamath, A., Lukacik, P., Powell, A., Strain-Damerell, C., Resnick, E., Krojer, T., Gehrtz, P., and Wild, C. (2021, January 13). PanDDA Analysis Group Deposition of SARS-CoV-2 Main Protease Fragment Screen. Available online: https:\/\/doi.org\/https:\/\/doi.org\/10.2210\/pdb5RET\/pdb.","DOI":"10.2210\/pdb5ret\/pdb"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/0263-7855(96)00018-5","article-title":"VMD: Visual molecular dynamics","volume":"14","author":"Humphrey","year":"1996","journal-title":"J. Mol. Graph."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1137\/090771806","article-title":"Finding structure with randomness: Probabilistic algorithms for constructing approximate matrix decompositions","volume":"53","author":"Halko","year":"2011","journal-title":"SIAM Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.compbiolchem.2018.01.009","article-title":"A random version of principal component analysis in data clustering","volume":"73","author":"Palese","year":"2018","journal-title":"Comput. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An open chemical toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminform."},{"key":"ref_42","first-page":"23","article-title":"In silico predictive model to determine vector-mediated transport properties for the blood\u2013brain barrier choline transporter","volume":"7","author":"Shityakov","year":"2014","journal-title":"Adv. Appl. Bioinform. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 update: Improved access to chemical data","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15\u2013ligand discovery for everyone","volume":"55","author":"Sterling","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4417","DOI":"10.1038\/s41467-020-18233-x","article-title":"Both Boceprevir and GC376 efficaciously inhibit SARS-CoV-2 by targeting its main protease","volume":"11","author":"Fu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4282","DOI":"10.1038\/s41467-020-18096-2","article-title":"Feline coronavirus drug inhibits the main protease of SARS-CoV-2 and blocks virus replication","volume":"11","author":"Vuong","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Fischer, A., Sellner, M., Neranjan, S., Smie\u0161ko, M., and Lill, M.A. (2020). Potential Inhibitors for Novel Coronavirus Protease Identified by Virtual Screening of 606 Million Compounds. Int. J. Mol. Sci., 21.","DOI":"10.26434\/chemrxiv.11923239"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Bz\u00f3wka, M., Mitusi\u0144ska, K., Raczy\u0144ska, A., Samol, A., Tuszy\u0144ski, J.A., and G\u00f3ra, A. (2020). Structural and Evolutionary Analysis Indicate That the SARS-CoV-2 Mpro Is a Challenging Target for Small-Molecule Inhibitor Design. Int. J. Mol. Sci., 21.","DOI":"10.1101\/2020.02.27.968008"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1021\/ci00057a005","article-title":"SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules","volume":"28","author":"Weininger","year":"1988","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1126\/science.1244142","article-title":"Serial femtosecond crystallography of G protein\u2013coupled receptors","volume":"342","author":"Liu","year":"2013","journal-title":"Science"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ccr.2005.01.007","article-title":"Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl","volume":"7","author":"Weisberg","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Tazikeh-Lemeski, E., Moradi, S., Raoufi, R., Shahlaei, M., Janlou, M.A.M., and Zolghadri, S. (2020). Targeting SARS-COV-2 non-structural protein 16: A virtual drug repurposing study. J. Biomol. Struct. Dyn., 1\u201314.","DOI":"10.1080\/07391102.2020.1779133"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.drudis.2015.05.005","article-title":"Covalent inhibitors in drug discovery: From accidental discoveries to avoided liabilities and designed therapies","volume":"20","author":"Bauer","year":"2015","journal-title":"Drug Discov. Today"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrd3410","article-title":"The resurgence of covalent drugs","volume":"10","author":"Singh","year":"2011","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1136\/bmj.1.5344.1521","article-title":"Ethacrynic Acid: A New Oral Diuretic","volume":"1","author":"Melvin","year":"1963","journal-title":"Br. Med. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1097\/MJT.0b013e318195e460","article-title":"The clinical pharmacology of ethacrynic acid","volume":"16","author":"Molnar","year":"2009","journal-title":"Am. J. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6832","DOI":"10.1021\/jm0501782","article-title":"A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods","volume":"48","author":"Kaeppler","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3851\/IMP1480","article-title":"Lack of efficacy of aurintricarboxylic acid and ethacrynic acid against vaccinia virus respiratory infections in mice","volume":"20","author":"Smee","year":"2010","journal-title":"Antivir. Chem. Chemother."},{"key":"ref_59","first-page":"1186","article-title":"Pharmakokinetics and bioavailability study of ethacrynic acid as a modulator of drug resistance in patients with cancer","volume":"270","author":"Lacreta","year":"1994","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/jcp.1041590212","article-title":"Changes in mitochondrial shape and distribution induced by ethacrynic acid and the transient formation of a mitochondrial reticulum","volume":"159","author":"Soltys","year":"1994","journal-title":"J. Cell. Physiol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/1\/106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:10:50Z","timestamp":1760159450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/1\/106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,13]]},"references-count":60,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["v13010106"],"URL":"https:\/\/doi.org\/10.3390\/v13010106","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,13]]}}}