Atazanavir inhibits SARS-CoV-2 replication and pro-inflammatory cytokine production
bioinformatics therapeutics virology
Authors: Fintelman-Rodrigues et al. Link to paper: https://doi.org/10.1101/2020.04.04.020925
Journal/ Pre-Print: bioRxiv preprint
Key Words: Antiviral drug; protease inhibitor; viral replication; cytokines
1. Atazanavir binds to and inhibits the cysteine protease activity of the major protease of SARS-CoV-2.
2. Atazanavir, alone or with Ritonavir, inhibits SARS-CoV-2 viral replication in a human lung epithelial cell line. with a high CC50/EC50 level.
3. Atazanavir, alone or with Ritonavir, inhibits SARS-CoV-2 viral replication and secretion of pro-inflammatory cytokines in primary human monocytes.
The study finds, by molecular modelling and molecular dynamics, that the clinically-approved anti-HIV drug Atazanavir can bind to the major protease (Mpro) of SARS-CoV-2, and demonstrates in vitro that it inhibits the cysteine protease activity of cell lysates containing Mpro. Reduced viral replication is shown in cells of the human epithelial pulmonary cell line (A549) infected with SARS-CoV-2 and then treated with Atazanavir, alone or in combination with another anti-retroviral drug Ritonavir, comparable to that achieved by chloroquine. When human monocytes were infected with SARS-CoV-2, their secretion of IL-6 and TNF-alpha was significantly reduced by treatment with the Atazanavir/Ritonavir combination, in addition to reduced viral replication.
IMPACT FOR SARS-COV2/COVID19 RESEARCH EFFORTS
- Understand the virology and/or cell biology of SARS-CoV2/COVID19
- Inhibition of SARS-CoV2/COVID19 replication
- Treatment of SARS-CoV2/COVID19 positive individuals
· In silico computational simulation study
· In vitro assays
· Cell culture, virology study
STRENGTHS AND LIMITATIONS OF THE PAPER
Novelty: The first description of the major protease (Mpro) of SARS-CoV-2 as a target for the anti-retroviral Atazanavir.
Standing in the field: This study concurs with previous studies of the effect of anti-retrovirals on SARS-CoV via targeting the major protease
Appropriate statistics: Statistics are mostly appropriate when included, although error bars are not included in all figures (e.g. Fig 6A) and some figures seem to contain less than three data points (e.g. Fig 7B).
Viral model used: Live SARS-CoV-2 strain (isolated in Rio de Janeiro, Brazil from a nasopharyngeal swab)
Translatability: Atazanavir is already approved for use in HIV, and has been reported to reach the lung after I.V. administration, so ready to trial in COVID-19 patients.
1. The authors only tested the drug efficacy in isolated cells in vitro. Is the concentration used comparable to that reaching the lung after administration of standard therapeutic dose, or much higher? The authors didn’t comment on this.
2. Comparison between Atazanavir and Lopinavir binding affinity is only done in silico by modelling and prediction, but not via any binding affinity assays.
3. No in vitro data or cell culture data on comparison between the antiviral effects of Atazanavir and Lopinavir.
4. Did not explain why Atazanavir and Ritonavir cocktail has a higher EC50 than Atazanavir alone to inhibit SARS-CoV-2