Synergistic effect between NF-κB inhibitors and zinc in vitro reducing ACE2 expression

Researchers at National Taiwan University Hospital in Taipei have conducted a study demonstrating the potential effectiveness of a novel drug combination at reducing morbidity and mortality in coronavirus disease 2019 (COVID-19).

In a study using two human cell lines, a combination of the clinical drugs triclabendazole and emetine effectively suppressed expression of the host cell receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).

Furthermore, this suppressive effect was enhanced by the addition of zinc sulfate, suggesting that zinc supplementation might further increase the potential clinical application of the drug combination for COVID-19 prevention and treatment.

The authors point out that zinc supplements are already inexpensive and widely available and that triclabendazole and emetine are already clinically approved by the U.S Food and Drug Administration (FDA).

“Therefore, triclabendazole or emetine in combination with zinc should be considered as additional study arm for COVID-19 clinical trials,” writes Bor-Ru Lin and the team.

A pre-print version of the research paper is available on the bioRxiv* server, while the article undergoes peer review.

Severe disease is associated with cytokine storm

The clinical course of COVID-19 is highly variable, ranging from asymptomatic to severe disease characterized by acute respiratory distress syndrome (ARDS) and multi-organ damage.

Severe disease is associated with a phenomenon called the cytokine storm, where the over-production of inflammatory peptides causes uncontrolled and fatal systemic inflammation.

To infect a host cell, SARS-CoV-2 uses a surface structure called the spike protein to bind to the host cell receptor angiotensin-converting enzyme 2 (ACE2). Agents that target this binding of the spike to ACE2 have therefore been investigated as potential preventive and treatment approaches, although their clinical efficacy and safety is still being assessed.

Research has shown that COVID-19 patients with severe disease have uncontrolled cytokine release that is related to activation of the proinflammatory NF-κB signaling pathway.

Therefore, inhibition of the NF-(B signaling pathway is also considered a potential therapeutic approach to severe COVID-19.

Research has also indicated that the SARS-CoV-2 spike protein can activate the NF-κB pathway in alveolar epithelial cells and trigger the cytokine storm that is observed in severely ill patients.  

What did the researchers do?

To investigate whether this pathway plays a role in the regulation of ACE2, the researchers used a known inhibitor of NF-kB activation – pyrrolidine dithiocarbamate (PDTC) – to treat H322M and Calu-3 cell lines expressing endogenous ACE2.

The team found that PDTC decreased the expression of ACE2 in a dose- and time-dependent manner.

“These findings indicate that ACE2 expression is regulated by NF-kB signal pathway, and implicate that clinical drugs with the activity of NF-kB inhibition may exert beneficial effects against COVID-19,” writes Lin and colleagues.

Emetine and triclabendazole also reduced ACE2 expression

Studies have previously shown that the clinically approved antiprotozoal drug emetine and the anthelmintic drug triclabendazole can inhibit the NF-kB signaling pathway.

Next, the researchers showed that the expression of ACE2 was also reduced in a dose- and time-dependent manner in H322M cells treated with these drugs.

“These findings suggest that triclabendazole and emetine, FDA approved clinical drugs, exhibit anti-SARS-CoV-2 activity via ACE2 suppression to reduce viral infection,” writes Lin and colleagues.

Where does zinc come in?

The team says zinc has previously been shown to mediate antiviral effects, including reduced viral replication, preservation of antiviral immunity, and a reduced risk of hyperinflammation.

Observational studies have also reported that lower baseline zinc levels among hospitalized COVID-19 adults were associated with a higher risk of mortality, complications, and more extended hospital stay.

Furthermore, research has shown that zinc may possess antiviral and anti-inflammatory activity through disruption of NF‑κB signaling.

“Because zinc supplementation is a cost-efficient, globally available and simple to use option with little to no side effects, it has much potential in combination with other repurposed drugs against COVID-19 treatment,” says the team.

Next, the researchers investigated the effects of triclabendazole or emetine alone and the effects of combining them with zinc sulfate.

No significant reduction in ACE2 expression was observed when cells were treated with triclabendazole, emetine or zinc sulfate alone. However, a combination of all three did significantly reduce ACE2 expression.

A potential treatment for severe COVID-19

These findings suggest that a combination of repurposed inhibitors of NF-kB and zinc supplementation has the potential to prevent and treat severe COVID-19.

“The advantages of combination therapy include increased treatment efficacy, reduced dose and side effects of toxic drugs, prevention of the development of drug resistance, and reduced duration of treatment,” writes Lin and colleagues.

“Triclabendazole or emetine in combination with zinc should be considered as an additional study arm for COVID-19 clinical trials,” they conclude.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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Comments

  1. Yin-Kai Chen Yin-Kai Chen Taiwan says:

    Indeed, our first bioRXiv preprint earlier pointed out that zinc sulfate plus azithromycin shared similar potential and mechanism.
    www.biorxiv.org/.../2021.01.19.427206v1

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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