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

    Authors: Carlos A. Fuzo; Ronaldo B. Martins; Thais F.C. Fraga-Silva; Martin K. Amstalden; Thais Canassa-DeLeo; Juliano P. Souza; Thais M. Lima; Lúcia H. Faccioli; Suzelei C. França; Vânia L.D. Bonato; Eurico A. Neto; Marcelo Dias-Baruffi

    doi:10.1101/2021.04.20.439992 Date: 2021-04-20 Source: bioRxiv

    The global emergence of Covid-19 MESHD 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 MESHD, 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 MESHD cells; bound with high-affinity energy to viral molecular targets such as main protease PROTEIN ( Mpro PROTEIN) 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 HGNC ( IL-6 HGNC) secretion in SARS-CoV-2-infected MESHD human cell lines. Interestingly, celastrol acted in a concentration-dependent manner, with undetectable signs of cytotoxicity MESHD. Therefore, celastrol is a promising lead drug candidate to treat Covid-19 MESHD due to its ability to suppress SARS-CoV-2 replication and IL-6 HGNC production in infected cells, two critical events in the pathophysiology of this disease.

    SARS-CoV-2 proteases cleave IRF3 HGNC and critical modulators of inflammatory pathways ( NLRP12 HGNC and TAB1): implications for disease presentation across species and the search for reservoir hosts.

    Authors: Mehdi Moustaqil; Emma Ollivier; Hsin-Ping Chiu; Paulina Rudolffi-Soto; Sarah Van Tol; Christian Stevens; Akshay Bhumkar; Dominic J.B. Hunter; Alexander N. Freiberg; David Jacques; Benhur Lee; Emma Sierecki; Yann Gambin

    doi:10.1101/2020.06.05.135699 Date: 2020-06-05 Source: bioRxiv

    The genome of SARS-CoV-2 ( SARS2 MESHD) encodes for two viral proteases ( NSP3 PROTEIN NSP3 HGNC/ papain-like protease PROTEIN and NSP5 HGNC NSP5 PROTEIN/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 PROTEIN NSP3 HGNC and NSP5 HGNC NSP5 PROTEIN of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 MESHD NSP3 HGNC NSP3 PROTEIN and NSP5 PROTEIN NSP5 HGNC target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 PROTEIN NSP3 HGNC and NSP5 PROTEIN NSP5 HGNC on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 HGNC NSP3 PROTEIN or NSP5 PROTEIN NSP5 HGNC, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 PROTEIN NSP3 HGNC or NSP5 HGNC NSP5 PROTEIN: IRF-3 HGNC, and NLRP12 HGNC and TAB1, respectively. Direct cleavage of IRF3 HGNC by NSP3 HGNC NSP3 PROTEIN could explain the blunted Type- I IFN response seen during SARS-CoV-2 infection MESHD SARS-CoV-2 infection MESHDs while NSP5 PROTEIN NSP5 HGNC mediated cleavage of NLRP12 HGNC and TAB1 point to a molecular mechanism for enhanced production of IL-6 HGNC and inflammatory response observed in COVID-19 MESHD patients. Surprisingly, both NLRP12 HGNC and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 MESHD and should facilitate the search or development of more effective animal models for severe COVID-19 MESHD. Finally, we discovered that one particular species of bats, Davids Myotis, possesses the five cleavage sites found in humans for NLRP12 HGNC, TAB1 and IRF3 HGNC. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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