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Clinical manifestations of this disease vary from asymptomatic to lethal, and the symptomatic form can be associated with cytokine storm and hyperinflammation. In face of the urgent demand for effective drugs to treat COVID\u201019, we have searched for candidate compounds using in silico approach followed by experimental validation. Here we identified celastrol, a pentacyclic triterpene isolated from\n                    <jats:italic>Tripterygium wilfordii<\/jats:italic>\n                    Hook F, as one of the best compounds out of 39 drug candidates. Celastrol reverted the gene expression signature from severe acute respiratory syndrome coronavirus 2\u00a0(SARS\u2010CoV\u20102)\u2010infected cells and irreversibly inhibited the recombinant forms of the viral and human cysteine proteases involved in virus invasion, such as M\n                    <jats:sup>pro<\/jats:sup>\n                    (main protease), PL\n                    <jats:sup>pro<\/jats:sup>\n                    (papain\u2010like protease), and recombinant human cathepsin L. Celastrol suppressed SARS\u2010CoV\u20102 replication in human and monkey cell lines and decreased interleukin\u20106 (IL\u20106) secretion in the SARS\u2010CoV\u20102\u2010infected human cell line. Celastrol acted in a concentration\u2010dependent manner, with undetectable signs of cytotoxicity, and inhibited in vitro replication of the parental and SARS\u2010CoV\u20102 variant. Therefore, celastrol is a promising lead compound to develop new drug candidates to face COVID\u201019 due to its ability to suppress SARS\u2010CoV\u20102 replication and IL\u20106 production in infected cells.\n                  <\/jats:p>","DOI":"10.1002\/ddr.21982","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T01:44:04Z","timestamp":1661132644000},"page":"1623-1640","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Celastrol: A lead compound that inhibits SARS\u2010CoV\u20102 replication, the activity of viral and human cysteine proteases, and virus\u2010induced IL\u20106 secretion"],"prefix":"10.1002","volume":"83","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3198-9969","authenticated-orcid":false,"given":"Carlos A.","family":"Fuzo","sequence":"first","affiliation":[{"name":"Departamento de An\u00e1lises Cl\u00ednicas, Toxicol\u00f3gicas e Bromatol\u00f3gicas,\u00a0Faculdade de Ci\u00eancias Farmac\u00eauticas de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8902-5962","authenticated-orcid":false,"given":"Ronaldo B.","family":"Martins","sequence":"additional","affiliation":[{"name":"Departamento de Biologia Celular e Molecular e Bioagentes Patog\u00eanicos, Faculdade de Medicina de Ribeir\u00e3o Preto Universidade de S\u00e3o Paulo Ribeir\u00e3o Preto S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais F. 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