The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produces inflammatory cytokine storms. But an FDA-approved anti-rheumatic drug, Auranofin, used to treat autoimmune and infectious diseases, may also help serve as an antiviral treatment for COVID-19 infection.
In a new research article, Karine Sonzogni-Desautels and Momar Ndao of the Research Institute of the McGill University Health Centre in Canada make a case for Auranofin based on the drug’s mechanism of action and anti-inflammatory properties via the NF-kBIL-6-STAT3 signaling pathway.
The researchers write:
“An orally-administered FDA-approved drug with anti-inflammatory and anti-SARS-CoV-2 properties with an acceptable toxicity profile would offer significant benefits for the control of the COVID-19 pandemic.”
The study “Will Auranofin Become a Golden New Treatment Against COVID-19?” was recently published in the medical journal Frontiers in Immunology.
Auranofin inhibits several key players in the NF-kB-IL-6-STAT3 signaling pathway
Auranofin helps minimize oxidative stress and increases cell survival by inhibiting the thioredoxin reductase enzyme.
Thioredoxin reductase is involved in regulating the transcription factor NF-kB, which promotes inflammation. By reducing thioredoxin reductase, Auranofin inhibits NF-kB-dependent gene expression.
Auranofin is advantageous for its ability to reduce IL-6 expression through inhibition of NF-kb in SARS-CoV-2 infected cells.
Prior research has implicated NF-kB with increased IL-6 expression. IL-6 is a proinflammatory cytokine and a key player in cytokine storms responsible for severe COVID-19 symptoms such as pulmonary fibrosis and multiple organ problems. More evidence strengthening this theory is that the SARS-CoV spike protein and nucleocapsid protein encourage NF-kB-dependent IL-6 expression.
Another way Auranofin inhibits NF-kB is by blocking the homodimerization of toll-like receptor (TLR) 4. TLR4 is associated with SARS-CoV-2–induced inflammatory responses. In addition, Auranofin can inhibit TLR3, another toll-like receptor observed during SARS-CoV-2 infection.
It also acts as an inhibitor of STAT3 and Janus kinase 1 (JAK1) — a kinase in charge of IL-6-induced phosphorylation.
Auranofin shows evidence of antiviral properties
The inhibition of thioredoxin reductase may inhibit the spike-ACE2 interaction required for SARS-CoV-2 entry in host cells. In addition, Auranofin stops viral replication by inhibiting SARS-CoV and SARS-CoV-2 papain-like proteases.
In one study, SARS-CoV-2 RNA decreased by 70% 24 hours after administering auranofin treatment. After 48 hours, Auranofin caused an 85% reduction in SARS-CoV-2 RNA.
“To explain its inhibitory effect on viral replication, it was hypothesized that Auranofin could affect SARS-CoV-2 protein synthesis partially due to its action on the redox milieu via inhibition of thioredoxin reductase. We recommend to further investigate in vitro the potential direct antiviral action of Auranofin during SARS-CoV-2 infection to better understand its mechanism of action,” wrote the researchers.
Auranofin’s ability to inhibit viral replication has been seen with other viruses such as the Zika virus, the Venezuelan equine encephalitis virus, and the chikungunya virus. In addition, several HIV studies also show evidence of Auranofin’s ability to reduce infection via inhibition of thioredoxin reductase.
Because human cells contain mitochondrial thioredoxin reductase, low concentrations of Auranofin are effective in inhibiting it. The end result is increased mitochondrial membrane permeability transition, loss of mitochondrial membrane potential, the release of cytochrome C, and apoptosis.
Auranofin is safe and generally well-tolerated in humans
Auranofin is FDA-approved for treating rheumatoid arthritis with a good safety profile.
However, the drug does have some nonlife-threatening side effects that may require routine monitoring. For example, patients taking oral doses of Auranofin tend to report diarrhea and loose stools. Rashes and proteinuria are uncommon side effects.
Thrombocytopenia and bone marrow suppression are rare, but there is potential for Auranofin to affect the immune system with long-term use. For this reason, the researchers recommend administering Auranofin for short-term treatment.
In one clinical trial studying the safety of auranofin treatment, the most common adverse event was headaches. All others were mild and went away without requiring additional treatment.
“The advantages of auranofin treatment in SARS-CoV2 infections will prevail over potential toxicity for most patients, but we recommend administering auranofin under close medical supervision until safety data are available for COVID-19 patients,” concluded the team.
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