Celastrol: A lead compound that inhibits SARS-CoV-2 replication, the activity of viral and human cysteine proteases, and virus-induced IL-6 secretion

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Fuzo, Carlos A. ; Martins, Ronaldo B. ; Fraga-Silva, Thais F. C. ; Amstalden, Martin K. ; De Leo, Thais Canassa ; Souza, Juliano P. ; Lima, Thais M. ; Faccioli, Lucia H. ; Okamoto, Debora Noma ; Juliano, Maria Aparecida ; Franca, Suzelei C. ; Juliano, Luiz ; Bonato, Vania L. D. ; Arruda, Eurico ; Dias-Baruffi, Marcelo

• Tipo de documento: Artigo Científico
• Fonte: Drug Development Research; v. 83, n. 7, p. 18-pg., 2022-08-21.

Resumo

The global emergence of coronavirus disease 2019 (COVID-19) has caused substantial human casualties. 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-19, we have searched for candidate compounds using in silico approach followed by experimental validation. Here we identified celastrol, a pentacyclic triterpene isolated from Tripterygium wilfordii 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 (SARS-CoV-2)-infected cells and irreversibly inhibited the recombinant forms of the viral and human cysteine proteases involved in virus invasion, such as M-pro (main protease), PLpro (papain-like protease), and recombinant human cathepsin L. Celastrol suppressed SARS-CoV-2 replication in human and monkey cell lines and decreased interleukin-6 (IL-6) secretion in the SARS-CoV-2-infected human cell line. Celastrol acted in a concentration-dependent manner, with undetectable signs of cytotoxicity, and inhibited in vitro replication of the parental and SARS-CoV-2 variant. Therefore, celastrol is a promising lead compound to develop new drug candidates to face COVID-19 due to its ability to suppress SARS-CoV-2 replication and IL-6 production in infected cells. (AU)

• Processo FAPESP: 20/05270-0 - Papel da morte de células epiteliais alveolares humanas na inflamação causada pelo 2019-nCoV e comprovação por análise do transcriptoma de pacientes infectados
• Beneficiário: Vânia Luiza Deperon Bonato
• Modalidade de apoio: Auxílio à Pesquisa - Regular