Wnt/Beta-Catenin Signaling Inhibitors Can Be Used As Antivirals Against SARS-CoV-2 And Possibly Other Viruses!
Nikhil Prasad Fact checked by:Thailand Medical News Team Mar 06, 2024 1 month, 3 weeks, 10 hours, 55 minutes ago
COVID-19 News: The ongoing threat of emerging viruses, such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), highlights the urgent need for innovative antiviral strategies. In a groundbreaking study conducted by the University of Alberta research team and covered in this
COVID-19 News report, a new class of antiviral drugs has been identified, offering promising possibilities for preventing or treating infections during future viral outbreaks. This research revolves around targeting the Wnt/β-catenin signaling pathway, which has proven effective in inhibiting SARS-CoV-2 replication and, remarkably, exhibits broad-spectrum antiviral activity against other pathogenic RNA viruses.
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Wnt/β-catenin signaling pathway associated genes are upregulated during SARS-CoV-2 infection.
A Calu-3 cells were infected with SARS-CoV-2 for 6-, 18-, 24- or 48-h after which total RNA was extracted from cells. Relative levels of c-myc, c-jun, AR, ESR1, ATF3, LEF1, TCF1 and TCF4 were determined by qRT-PCR. Two-way ANOVA with Bonferroni post-hoc tests were used to determine significance between mock and SARS-CoV-2 infected samples. B As a positive control for induction of Wnt target genes, Calu-3 cells were treated with the Wnt agonist II (SKL2001, 40 μM) or DMSO alone for 6-, 18-, 24- or 48-h after which total RNA was extracted from cells. Relative levels of c-myc, c-jun, AR, ESR1, ATF3, LEF1, TCF1 and TCF4 were determined by RT-qPCR. Two-way ANOVA with Bonferroni post-hoc tests were used to determine significance between DMSO and SKL2001-treated samples. C Total RNA including small RNAs were extracted from infected cells at 24-h post-infection (hpi) and was subjected to qRT-PCR analysis to determine relative levels of miRNAs (normalized to snRNU6). The average relative levels of miRNAs from three independent experiments are shown. D Cell lysates harvested at 24 hpi were processed for immunoblot analyses with antibodies to SARS-CoV-2 spike protein, β-catenin, catalase, PEX2, PEX7, PEX11B, PEX13, PEX19 and actin.
The Interplay of Wnt/β-Catenin Signaling and Viral Infection
The study builds upon previous research demonstrating how HIV manipulates the Wnt/β-catenin signaling pathway to evade the immune response by suppressing the production of peroxisomes and interferon. Similarly, the researchers hypothesized that SARS-CoV-2, an RNA virus like HIV, might exploit the same pathway to counteract the body's antiviral defenses. The investigation involved testing 40 existing drugs, originally designed for cancer treatment, that target the Wnt/β-catenin signaling pathway.
Key Findings and Antiviral Potential
Out of the 40 drugs tested, three demonstrated significant efficacy in reducing the viral load of SARS-CoV-2, showcasing a
potential breakthrough in antiviral therapeutics. The lead author, Dr Tom Hobman, emphasized the notable outcomes, including a remarkable 10,000-fold reduction in virus production observed in vitro. Furthermore, the tested drugs exhibited efficacy in a mouse model, preventing severe weight loss and promoting quicker recovery.
Mechanism of Action and Implications
The Wnt/β-catenin signaling pathway is crucial for the replication of SARS-CoV-2 and other pathogenic RNA viruses. By inhibiting this pathway, the researchers observed enhanced peroxisome formation and increased interferon production, key components of the immune response. The drugs tested not only reduced viral replication but also showed promise in limiting inflammation and clinical symptoms.
Prophylactic and Therapeutic Potential
The proposed treatment strategy involves a short course of these antiviral drugs for individuals exposed or exhibiting early symptoms during a viral outbreak. This approach aims to prime peroxisome levels, mitigating the severity and spread of the disease. Notably, the drugs exhibit their antiviral effects only in the presence of viral infection, minimizing the risk of interferon production in the absence of infection.
Wnt/β-Catenin Inhibitors Against Emerging Variants
Given the ongoing evolution of viral variants, the researchers evaluated the effectiveness of Wnt/β-catenin inhibitors against different strains of SARS-CoV-2. Encouragingly, the inhibitors displayed efficacy against not only early variants but also more contemporary variants, including the concerning variants of concern (VOCs), such as alpha, beta, gamma, delta, and omicron.
Peroxisome Proliferation and IFN Response
The researchers investigated the underlying mechanism of action by studying peroxisome proliferation and its impact on the interferon (IFN) response. Wnt/β-catenin inhibitors were found to significantly increase peroxisome density, highlighting their potential to enhance the host's innate immune response. Additionally, these inhibitors potentiated the production of both type I and type III interferons, further reinforcing their antiviral effects.
In Vivo Efficacy and Safety
To assess the in vivo efficacy and safety of Wnt/β-catenin inhibitors, the researchers conducted experiments in mice infected with SARS-CoV-2. Despite challenges with the toxicity of some drugs, notably Pyrvinium, two inhibitors, KYA1797K and E7449, demonstrated significant reduction in viral load, protection against weight loss, and mitigation of lung injury. Importantly, E7449 exhibited superior efficacy and low cytotoxicity, making it a promising candidate for clinical application.
Broad-Spectrum Antiviral Activity
Extending their investigation beyond SARS-CoV-2, the researchers explored the broad-spectrum antiviral activity of Wnt/β-catenin inhibitors against other RNA viruses. Encouragingly, these inhibitors demonstrated effectiveness against seasonal human coronaviruses (HCOV-NL63 and HCOV-229E), the flavivirus Zika virus, and the alphavirus Mayaro virus. This discovery highlights the potential of Wnt/β-catenin inhibitors as a versatile tool against various viral infections.
Thailand
Medical News would like to add that there are a number of phytochemicals extracted from certain herbs that can also function as Wnt/Beta-Catenin signaling inhibitors and have proven safety and non-toxic profiles.
Conclusion
The research conducted by the University of Alberta research team introduces a groundbreaking approach to antiviral therapeutics by targeting the Wnt/β-catenin signaling pathway. The identified class of drugs not only exhibits potent antiviral effects against SARS-CoV-2 but also demonstrates broad-spectrum activity against other pathogenic RNA viruses. The findings open up new possibilities for the development of prophylactic and early-stage treatments for viral infections, providing a promising avenue to address current and future viral outbreaks. As clinical trials progress, Wnt/β-catenin inhibitors may emerge as a crucial component in the armamentarium against viral diseases, heralding a new era in antiviral drug development.
The study findings were published in the peer reviewed journal: NPJ Viruses (Nature).
https://www.nature.com/articles/s44298-024-00018-4
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