Activation of Peroxiredoxin 1 by Fluvastatin Effectively Protects from Inflammation and SARS-CoV-2
drug discovery/repurposing immunology/immunity therapeutics
Authors: Zhang et al.
Journal/ Pre-Print: CellPress Cell Metabolism under review
Tags: Immunology/Immunity, Therapeutics, Drug discovery/ Drug repurposing
1. Identified that Fluvastatin, a cholesterol-lowering drug, binds to and is an effective and selective agonist of PRDX1, an antioxidant enzyme.
2. Activation of PRDX1 with Fluvastatin reduces intracellular ROS and reduces proinflammatory responses in cell culture.
3. Fluvastatin inhibited SARS-CoV-2 infection in Vero E6 cells both during full-time treatment and post-entry treatment.
The study investigates the potential anti-inflammatory and antiviral effect of a repurposed statin drug Fluvastatin in SARS-CoV-2 infection. The authors demonstrate that Fluvastatin is a selective agonist of PRDX1, and reveal direct ligand binding using NMR titration, SPR and crystallography. They also suggest that Fluvastatin can activate PRDX1, which removes ROS and suppresses LPS-induced inflammation. Finally, they show that Fluvastatin can inhibit growth of SARS-CoV-2 in Vero E6 cells.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19: how it leads to inflammation
Clinical symptoms and pathogenesis of SARS-Cov2/COVID19: How cytokine storm may be triggered hence leads to COVID19 clinical symptom
Treat of SARS-CoV2/COVID19 positive individuals: New/repurposed potential antiviral drug
· In vitro study (in vitro and cell culture)
Strengths and limitations of the paper
Novelty: Identification of Fluvastatin, a pre-existing drug, as a novel agonist of PRDX1, an antioxidant enzyme, which may be used for antiviral purpose.
Standing in the field: Support the effect of Fluvastatin as a cardiovascular drug.
Appropriate statistics: Statistics is appropriate when applied. 3 independent experiments are done for statistics significance.
Viral model used: SARS-CoV-2 (origin unclear)
Translatability: Identification and early (laboratory testing) stage of a new/repurposed antiviral drug Fluvastatin. Can potentially be studied further in human lung cell culture, and if really showing promising effect, in animal models.
· Viral inhibition is only studied within 24hpi. Longer term effect needed to be investigated.
· Cell lines such as Vero and HeLa are used for all cell culture experiments (inhibition of ROS, pro-inflammation, viral replication), which does not represent the real infection situation.
· Pro-inflammatory responses more specific to viruses need to be studied. Explored the attenuation of LPS induced pro-inflammatory response, which models bacterial but NOT viral infection.
· Could not rule out that the inhibition of SARS-CoV-2 by Fluvastatin could also be due to effect on targets other than PRDX1.
· Virologic assay is poorly described. Viral growth is measured by fluorescence intensity, which only shows production of a certain viral protein. vRNA level should have also been measured.