Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production

Fintelman-Rodrigues, Natália; Sacramento, Carolina Q; Lima, Carlyle Ribeiro; Souza-Silva, Franklin; Ferreira, André C.; Mattos, Mayara; Freitas, Caroline de; Soares, Vinícius Cardoso; Dias, Suelen da Silva Gomes; Temerozo, Jairo R.; Miranda, Milene Dias; Matos, Aline da Rocha; Bozza, Fernando A.; Carels, Nicolas; Alves, Carlos Roberto; Siqueira, Marilda M.; Bozza, Patrı́cia T.; Souza, Thiago Moreno L.

doi:10.1128/aac.00825-20

Cited by 113 publications

(122 citation statements)

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“…These results agree with previous reports in which HIV protease inhibitors lacked detectable activity against 3CL pro in vitro [ 18 , 19 , 20 ]. In contrast, other early studies found that some HIV protease inhibitors block SARS-CoV-2 replication in cell culture [ 35 , 36 , 37 ]. However, Hattori and co-workers recently demonstrated that these findings were likely false positives due to compound cytotoxicity [ 38 ].…”

Section: Discussionmentioning

confidence: 86%

“…Human immunodeficiency virus (HIV) protease inhibitors, particularly lopinavir and nelfinavir, have been reported to inhibit the replication of SARS-CoV-2 in cell culture [ 35 , 36 , 37 ]. However, other groups have reported that HIV protease inhibitors do not block SARS-CoV-2 3CL pro in vitro, even at the maximal concentration tested (20 or 100 µM) [ 18 , 19 , 20 ].…”

Section: Resultsmentioning

confidence: 99%

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Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CLpro Inhibitors

Rawson

Duchon

Nikolaitchik

et al. 2021

Viruses

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The 3C-like protease (3CLpro) of SARS-CoV-2 is considered an excellent target for COVID-19 antiviral drug development because it is essential for viral replication and has a cleavage specificity distinct from human proteases. However, drug development for 3CLpro has been hindered by a lack of cell-based reporter assays that can be performed in a BSL-2 setting. Current efforts to identify 3CLpro inhibitors largely rely upon in vitro screening, which fails to account for cell permeability and cytotoxicity of compounds, or assays involving replication-competent virus, which must be performed in a BSL-3 facility. To address these limitations, we have developed a novel cell-based luciferase complementation reporter assay to identify inhibitors of SARS-CoV-2 3CLpro in a BSL-2 setting. The assay is based on a lentiviral vector that co-expresses 3CLpro and two luciferase fragments linked together by a 3CLpro cleavage site. 3CLpro-mediated cleavage results in a loss of complementation and low luciferase activity, whereas inhibition of 3CLpro results in 10-fold higher levels of luciferase activity. The luciferase reporter assay can easily distinguish true 3CLpro inhibition from cytotoxicity, a powerful feature that should reduce false positives during screening. Using the assay, we screened 32 small molecules for activity against SARS-CoV-2 3CLpro, including HIV protease inhibitors, HCV protease inhibitors, and various other compounds that have been reported to inhibit SARS-CoV-2 3CLpro. Of these, only five exhibited significant inhibition of 3CLpro in cells: GC376, boceprevir, Z-FA-FMK, calpain inhibitor XII, and GRL-0496. This assay should greatly facilitate efforts to identify more potent inhibitors of SARS-CoV-2 3CLpro.

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Section: Discussionmentioning

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CLpro Inhibitors

Rawson

Duchon

Nikolaitchik

et al. 2021

Viruses

View full text Add to dashboard Cite

show abstract

“…For animal experimentation, appropriate BSL-3 platforms are even more rare. In Brazil, for instance, the laboratories that excelled at generating relevant and important knowledge during epidemics of Zika, dengue and Chikungunya have had to face long waiting lines to access BLS-3 facilities in their own or collaborating institutions [ 5 , 6 ] (preprints: [ [7] , [8] , [9] , [10] , [11] ]). Ultimately, this has had the effect of concentrating the ability to advance the preclinical development of vaccines and antivirals to the richest countries.…”

Section: Biosafety Level Requirements During Epidemicsmentioning

confidence: 99%

The COVID-19 pandemics and the relevance of biosafety facilities for metagenomics surveillance, structured disease prevention and control

Souza¹,

Morel²

2021

Biosafety and Health

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The 2019 coronavirus disease (COVID-19) pandemic represents an enormous challenge to all countries, regardless of their development status. The manipulation of its etiologic agent SARS-CoV-2 requires a biosafety containment level 3 laboratories (BSL-3) to understand virus biology and in vivo pathogenesis as well as the translation of new knowledge into the preclinical development of vaccines and antivirals. As such, BSL-3 facilities should be considered an integral part of any public health response to emerging infectious disease prevention, control and management. Differently from BSL2, BSL-3 units vary considerably along the range from industrialized to the least developed countries. Innovative Developing Countries (IDCs) such as Brazil, which excelled at controlling the 2015–2017 Zika epidemic, had to face a serious flaw in its disease control and prevention structure: the scarcity and uneven geographic distribution of its BSL-3 facilities, including those for preclinical animal experimentation.

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“…Atazanavir and fluvoxami,ne for example, include both pharmacogenetics information and prescription recommendations. A molecular dynamics analysis and in vitro experiments showed that atazanavir, a protease inhibitor against human immunodefiency virus (HIV), could inhibit SARS-CoV-2 replication, alone or in combination with ritonavir 9 . Atazanavir inhibits the hepatic uridine diphosphate glucuronosyltransferase family 1 member A1 (UGT1A1), thereby preventing the glucuronidation and elimination of bilirubin 10 .…”

Section: Introductionmentioning

confidence: 99%

Exploration of interethnic variation and repurposed drug efficacy in the treatment of SARS-CoV-2 Infection (COVID-19)

Aa¹

2021

Preprint

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The COVID-19 global pandemic has led to repurposing of drugs, with little underlying evidence for treatment safety and efficacy. This may increase complications for patients with acute viral respiratory infections. UGT1A1 and CYP2D6 enzymes are involved in the metabolism of atazanavir and fluvoxamine repurposed for COVID-19. This study aimed to elucidate the role of interethnic variation in these enzymes in the efficacy of repurposed drug therapies. A retrospective cohort of 101 Jordanian Arab samples were genotyped using Affymetrix DMET Plus Premier Package. Comprehensive global population genetic structure analyses were performed for CYP2D6 and UGT1A1 allele frequencies across multi-ethnic populations of over 131,000 global subjects from 417 published reports, revealing that Jordanian Arabs share the closest sequence homology to European and Near East populations. The East Asian populations have significantly over-representaiton of individuals with diplotype pairs for reduced atazanavir metabolism compared to the African populations and are more likely to show impaired UGT1A1 metabolism. East Asian populations are also 4.4x more likely to show impaired fluvoxamine metabolism than South Central Asian and Oceanian populations, and 8x more likely than other ancestry populations. The results here support previous findings that interethnic variation should be used for developing proper population-specific dosage guidelines.

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Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production

Cited by 113 publications

References 50 publications

Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CLpro Inhibitors

Development of a Cell-Based Luciferase Complementation Assay for Identification of SARS-CoV-2 3CLpro Inhibitors

The COVID-19 pandemics and the relevance of biosafety facilities for metagenomics surveillance, structured disease prevention and control

Exploration of interethnic variation and repurposed drug efficacy in the treatment of SARS-CoV-2 Infection (COVID-19)

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