Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

Fuzo, C. A.; Martins, R. B.; Fraga-Silva, T. F. C.; Amstalden, M. K.; Canassa-DeLeo, T.; Souza, J. P.; Lima, T. M.; Faccioli, L. H.; Franca, S. C.; Bonato, V. L. D.; Neto, E. A.; Dias-Baruffi, M.

doi:10.1101/2021.04.20.439992

bioRxiv · 10.1101/2021.04.20.439992

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

Fuzo, C. A.·Martins, R. B.·Fraga-Silva, T. F. C.·Amstalden, M. K.·Canassa-DeLeo, T.·Souza, J. P.·Lima, T. M.·Faccioli, L. H.·Franca, S. C.·Bonato, V. L. D.·Neto, E. A.·Dias-Baruffi, M.

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Abstract

The global emergence of Covid-19 has caused huge human casualties. Clinical manifestations of the disease vary from asymptomatic to lethal, and the symptomatic form can be associated with cytokine storm and non-homeostatic inflammatory response. In face of the urgent demand for effective drugs to treat Covid-19, we have searched for candidate compounds using a drug repurposing approach based on in silico analysis followed by biological validation. Here we identified celastrol, a pentacyclic triterpene isolated from Tripterygium wilfordii Hook F - a plant used in traditional Chinese medicine - as one of the best compounds out of 39 repurposed drug candidates. Celastrol reverted gene expression signature from SARS-CoV-2-infected cells; bound with high-affinity energy to viral molecular targets such as main protease (Mpro) and receptor-biding domain (RBD); inhibited SARS-CoV-2 replication in monkey (Vero and Vero-ACE2) and human (Caco-2 and Calu-3) cell lines; and decreased interleukin-6 (IL-6) secretion in SARS-CoV-2-infected human cell lines. Interestingly, celastrol acted in a concentration-dependent manner, with undetectable signs of cytotoxicity. Therefore, celastrol is a promising lead drug candidate to treat Covid-19 due to its ability to suppress SARS-CoV-2 replication and IL-6 production in infected cells, two critical events in the pathophysiology of this disease.

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Fuzo, C. A., Martins, R. B., Fraga-Silva, T. F. C., Amstalden, M. K., Canassa-DeLeo, T., Souza, J. P., Lima, T. M., Faccioli, L. H., Franca, S. C., Bonato, V. L. D., Neto, E. A., Dias-Baruffi, M.. 2021-04-20. Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation. https://doi.org/10.1101/2021.04.20.439992

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