Study Finds That Nitazoxanide Is A Potent Inhibitor of Human Seasonal Coronaviruses
Nikhil Prasad Fact checked by:Thailand Medical News Sep 16, 2023 7 months, 1 week, 4 days, 8 hours, 55 minutes ago
The Coronaviridae family comprises a diverse group of enveloped, positive-sense single-stranded RNA viruses responsible for a range of diseases in animals and humans. The family's rapid evolution is driven by high genomic nucleotide substitution rates and recombination events. Among these viruses, seven human coronaviruses (HCoVs) have been identified, including the seasonal HCoVs (sHCoVs) HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, which circulate globally, and the highly pathogenic SARS-CoV, MERS-CoV, and SARS-CoV-2.
While sHCoVs are responsible for a significant portion of common cold cases, they can also lead to severe lower respiratory infections and life-threatening diseases in certain individuals. Unfortunately, no specific treatment has been available for sHCoV infections.
This new study by researchers from the University of Rome Tor Vergata-Italy, Institute of Translational Pharmacology, CNR-Italy and Romark Institute of Medical Research, Tampa-USA explores the potential of the anti-infective drug
nitazoxanide as a potent antiviral agent against three human endemic coronaviruses: HCoV-229E, HCoV-NL63, and HCoV-OC43.
The Emergence of Human Coronaviruses
Human coronaviruses were initially discovered in the 1960s and were initially thought to cause mild diseases in humans. However, this perception changed dramatically in 2002 with the outbreak of Severe Acute Respiratory Syndrome (SARS) and in 2012 with the emergence of Middle East Respiratory Syndrome (MERS). These zoonotic infections resulted in high mortality rates, raising concerns about the potential of coronaviruses to cause severe diseases in humans. The most recent addition to this list is SARS-CoV-2, which emerged in late 2019 and has since caused a global pandemic with millions of confirmed cases and significant morbidity and mortality.
sHCoVs: The Common Cold Culprits
Among the human coronaviruses, sHCoVs are responsible for a substantial portion of common cold cases. These viruses can also cause severe lower respiratory infections, particularly in vulnerable populations such as infants, the elderly, and immunocompromised individuals. Additionally, sHCoVs have been associated with enteric and neurological diseases, and there is evidence suggesting their involvement in conditions like Kawasaki disease.
Each of the four sHCoVs (HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1) belongs to distinct taxonomic genera, and they use different receptors to enter host cells. Despite these differences, infection by all sHCoVs begins with the binding of the viral spike (S) glycoprotein to specific host receptors. This spike protein plays a crucial role in the coronavirus lifecycle.
The Role of the Spike Glycoprotein
The spike glycoprotein of coronaviruses is a trimeric fusion protein with multiple functions. After synthesis, the spike protein undergoes glycosylation in the endoplasmic reticulum (ER), where it is modified. Proper glycosylation is essential for the spike protein's function. During infection, the spike protein mediates attachment to host receptors and facilitates viral entry into host cells.
Nitazoxanide: A Broad-Spectrum Antiviral
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Nitazoxanide is a thiazolide originally developed as an antiprotozoal agent and used clinically to treat infectious gastroenteritis. Second-generation thiazolides have emerged as a promising class of broad-spectrum antiviral drugs. Nitazoxanide and its active metabolite, tizoxanide, have demonstrated efficacy against various RNA pathogens, including rotaviruses, hepatitis C, influenza, and parainfluenza viruses, both in laboratory studies and clinical settings.
Early research in 2007 indicated nitazoxanide's effectiveness against a canine strain of coronavirus. Subsequent studies demonstrated its potential against MERS-CoV and SARS-CoV-2, the virus responsible for COVID-19. Notably, nitazoxanide has been found to inhibit SARS-CoV-2 replication in multiple cell types and animal models. Clinical studies have also suggested potential benefits for COVID-19 patients, although results have varied.
Nitazoxanide's Mechanism of Action
The exact mechanism by which nitazoxanide exerts its antiviral activity against coronaviruses is not fully understood. However, recent research has shed light on its actions against sHCoVs.
Nitazoxanide was found to inhibit the replication of HCoV-229E, HCoV-NL63, and HCoV-OC43 in cell culture with remarkable potency, exhibiting IC50 values between 0.05 and 0.15 μg/mL and high selectivity indexes (>330). Importantly, nitazoxanide does not interfere with virus adsorption, entry, or uncoating. Instead, it acts at a postentry level, specifically targeting the maturation of the spike glycoprotein.
The spike glycoprotein's maturation process is crucial for the virus's lifecycle. Nitazoxanide disrupts this process by inhibiting terminal glycosylation of the spike protein at an Endo-H-sensitive stage, preventing its final processing. This effect may hinder the formation of progeny virus particles, potentially limiting the spread of the virus within the host.
Comparing Nitazoxanide to Other Antivirals
The antiviral activity of nitazoxanide against sHCoVs is comparable to that of remdesivir, a direct-acting antiviral (DAA) and potent RNA-dependent RNA polymerase (RdRp) inhibitor. Notably, remdesivir has shown some vulnerability to the emergence of drug-resistant mutations, both in vitro and in COVID-19 patients. Nitazoxanide, as a host-directed antiviral, is less likely to induce resistance.
Furthermore, nitazoxanide offers several advantages over remdesivir. It can be administered orally, making it a more accessible treatment option. Additionally, the drug has a well-established safety profile, having been used for decades as an antiprotozoal agent.
Future Directions and Conclusion
The emergence of SARS-CoV-2 variants and the ongoing challenges posed by seasonal HCoVs underscore the need for broad-spectrum antiviral drugs. Nitazoxanide, with its broad-spectrum anti-coronavirus activity, represents a promising candidate for the treatment of sHCoV infections. Future research may explore the potential synergistic effects of combining nitazoxanide with other antivirals, such as remdesivir, to maximize treatment efficacy.
While nitazoxanide shows great promise, the optimization of its formulation may be necessary to improve its clinical efficacy in treating COVID-19. Nonetheless, the drug's ability to interfere with spike glycoprotein maturation, a critical step in the coronavirus lifecycle, offers hope for the development of effective treatments against a range of human coronaviruses.
In conclusion, the study findings highlight nitazoxanide as a potent inhibitor of human seasonal coronaviruses, providing a valuable addition to the arsenal of antiviral treatments and potentially contributing to the management of future coronavirus-related diseases. Further research and clinical trials are warranted to fully explore nitazoxanide's potential in treating sHCoV infections and related conditions, ultimately improving public health outcomes in the face of emerging viral threats.
The study findings were published in the peer reviewed journal: Frontiers In Microbiology.
https://www.frontiersin.org/articles/10.3389/fmicb.2023.1206951/full
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