Peruvoside – Covid-19: A Broad-Spectrum Antiviral Targeting Viral Factory Formation and GBF1 Phosphorylation in Positive-Sense RNA Viruses

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Peruvoside is a natural compound that belongs to the class of cardiac glycosides, which are substances that can affect the heart muscle and rhythm. Peruvoside is extracted from the plant Cascabela thevetia, also known as yellow oleander or lucky nut, which is native to tropical America and widely cultivated as an ornamental plant.

Peruvoside has been used for decades as a treatment for heart failure, a condition in which the heart cannot pump enough blood to meet the body’s needs. Peruvoside works by inhibiting a protein called Na+/K+-ATPase, which regulates the balance of sodium and potassium ions in the cells. By blocking this protein, peruvoside increases the force and efficiency of the heart contractions, improving the blood flow and oxygen delivery.

However, peruvoside has also been shown to have another remarkable effect: it can prevent the spread of diverse medically important viruses, such as SARS-CoV-2, influenza, enterovirus, dengue, Zika, and hepatitis C. These viruses belong to different families and have different structures and modes of infection, but they all share a common feature: they rely on a cellular protein called GBF1 for their replication.

GBF1 is a protein that is involved in the formation and transport of vesicles, which are small membrane-bound sacs that carry materials within or outside the cells. GBF1 is especially important for the function of the Golgi apparatus, an organelle that modifies and sorts proteins and lipids for secretion or delivery to other parts of the cell.

Many viruses hijack GBF1 and use it to create their own vesicles, where they can replicate their genetic material and assemble new virus particles. These virus-containing vesicles then fuse with the cell membrane and release the newly formed viruses into the extracellular space, where they can infect other cells and spread the infection.

Peruvoside can disrupt this process by activating a signaling pathway that leads to the phosphorylation of GBF1. Phosphorylation is a chemical modification that can alter the shape and function of a protein. In this case, phosphorylated GBF1 becomes unable to form normal vesicles and instead causes the fragmentation of the Golgi apparatus. This impairs the viral replication and production, and reduces the viral load in the cells and tissues.

Positive-sense RNA viruses are notorious for inducing extensive rearrangements of intracellular membranes, such as the endoplasmic reticulum (ER) and Golgi apparatus, to create clusters of double-membrane vesicles (DMVs) or convoluted membranes.

These structures serve as crucial sites for viral genome replication, polyprotein processing, and progeny virion formation. While many antiviral compounds have been developed to target viral proteins or genomes within these membrane structures or the cytoplasm, few antivirals are designed to target host factors involved in modulating viral replication due to the potential for off-target effects.

In this context, the search for a broad-spectrum antiviral inhibitor with a well-characterized mechanism of action becomes crucial. Plant-derived saponin glycosides, known for their therapeutic use in treating cardiac failure and arrhythmia, have been found to exhibit antiviral activities against RNA and DNA viruses. However, the specific mechanisms underlying their antiviral effects remain largely unknown.

In this study, the researchers focused on peruvoside, a saponin glycoside, and investigated its potential as a broad-spectrum antiviral compound. They discovered that peruvoside’s antiviral activity is closely linked to intracellular calcium flux triggered by the compound. By examining its effects on various viruses from different families, the researchers aimed to elucidate the underlying mechanism of peruvoside’s antiviral action.

Peruvoside and Calcium Signaling

Peruvoside is known to exert a positive inotropic effect on cardiac muscle cells by increasing intracellular calcium concentration, thereby enhancing muscle contractility. It achieves this effect by specifically inhibiting the sodium potassium pump (Na+/K+ ATPase) located at the plasma membrane.

Binding of peruvoside to the extracellular binding site of the Na+/K+ ATPase α-subunit results in a loss of pump activity and an increase in cytosolic sodium. This, in turn, alters the function of the Na+/Ca2+ exchanger, leading to an elevation of intracellular free calcium (Ca2+).

Recent studies have suggested that the interaction between Na+/K+ ATPase and other signaling molecules, such as the tyrosine kinase Src and the epidermal growth receptor, forms a signaling complex that triggers a series of complex signaling cascades. Peruvoside’s binding to the Na+/K+ ATPase activates Src, which, in turn, transactivates the epidermal growth receptor and initiates signaling pathways involving Ras-mediated Raf-ERK1/2 kinase cascade, ultimately resulting in gene expression changes within the cell.

The Role of Calcium Flux and Golgi Vesiculation

In this study, the researchers found that peruvoside-induced intracellular calcium flux played a crucial role in its broad-spectrum antiviral activity. Intracellular calcium influx in the cytoplasm was observed upon peruvoside treatment. Previous studies have demonstrated that intracellular calcium flux can activate calcium/calmodulin-dependent kinases, including ERK1/2, which are involved in various growth-related pathways, including MAPK/ERK activation.

The researchers further demonstrated that peruvoside’s antiviral activity was significantly reduced when Src, CaMK1 (a calcium/calmodulin-dependent kinase), or ERK1/2 were inhibited. These findings indicate that the activation of calcium flux and subsequent signaling cascades involving Src, PLC kinase, CaMK1, and ERK1/2 are critical for peruvoside’s antiviral mechanism.

Moreover, the activation of ERK1/2 was found to induce Golgi vesiculation, leading to the disruption of the secretory pathway and impairing viral protein trafficking. This disruption ultimately interferes with viral replication and assembly processes that rely on proper intracellular membrane organization.

The researchers performed a series of experiments using different RNA and DNA viruses, including influenza A virus, respiratory syncytial virus (RSV), Zika virus, and herpes simplex virus type 1 (HSV-1).

In each case, peruvoside treatment resulted in a significant reduction in viral replication and progeny virus production. The antiviral effect was observed even when peruvoside was administered post-infection, suggesting that it interferes with late stages of the viral life cycle.

Further investigations revealed that peruvoside specifically targeted the phosphorylation of GBF1 (Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1), a key regulator of Golgi organization and vesicular trafficking. GBF1 phosphorylation is known to be crucial for its activity, and it has been linked to viral replication and secretion of various enveloped viruses.

Peruvoside treatment resulted in the inhibition of GBF1 phosphorylation, leading to the disruption of Golgi structure and function. This disruption was associated with the mislocalization of viral envelope glycoproteins, impaired trafficking of viral components, and reduced viral particle assembly and release.

Importantly, the researchers demonstrated that the antiviral activity of peruvoside was not restricted to specific virus families but was effective against both RNA and DNA viruses. This broad-spectrum activity suggests that peruvoside targets a host factor or pathway that is conserved among diverse viruses.

Conclusion

In conclusion, this study highlights peruvoside, a saponin glycoside compound, as a promising broad-spectrum antiviral agent. The researchers uncovered that peruvoside’s antiviral activity is linked to its ability to induce intracellular calcium flux and activate signaling pathways involving Src, CaMK1, and ERK1/2.

This activation leads to GBF1 phosphorylation inhibition, disrupting Golgi structure and impairing viral replication and assembly processes. The findings provide valuable insights into the molecular mechanisms underlying peruvoside’s antiviral effects and open avenues for further exploration of its therapeutic potential against a wide range of viral infections.


In deep….

Peruvoside: A Potential Treatment for COVID-19?

The coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented global health and economic crises, with over 200 million confirmed cases and over 4 million deaths worldwide as of August 2023. Despite the development and distribution of several vaccines, the emergence and spread of new variants of the virus pose a serious challenge to the effectiveness and availability of these preventive measures. Therefore, there is an urgent need for safe and effective antiviral drugs that can treat COVID-19 patients and reduce the severity and mortality of the disease.

One promising candidate for such a drug is peruvoside, a plant-based compound that is commonly used to treat heart failure. Peruvoside is a cardiac glycoside, a class of compounds that have the ability to inhibit the activity of an enzyme called Na+/K+-ATPase, which regulates the balance of sodium and potassium ions in cells. By doing so, cardiac glycosides can increase the force and efficiency of heart contractions, as well as modulate the electrical activity of the heart.

However, recent studies have shown that peruvoside and other cardiac glycosides also have potent antiviral properties against a wide range of medically important viruses, including SARS-CoV-2, the virus that causes COVID-19. According to a research paper published in Acta Pharmaceutica Sinica B in June 2023 , peruvoside can prevent the replication and production of up to 12 different viruses, all originating from different virus families.

These viruses include SARS-CoV-2, influenza A and B viruses, enteroviruses (which cause hand, foot and mouth disease), dengue virus, Zika virus, chikungunya virus, hepatitis C virus, human immunodeficiency virus (HIV), herpes simplex virus type 1 (HSV-1), human cytomegalovirus (HCMV), and Epstein-Barr virus (EBV).

The mechanism by which peruvoside exerts its antiviral effect is by targeting a protein called GBF1, which is essential for the formation and function of the Golgi apparatus, a cellular organelle that is involved in the processing and transport of proteins and lipids. The Golgi apparatus is also hijacked by many viruses to facilitate their replication and assembly.

Peruvoside acts on GBF1 by activating a signaling pathway that involves two other proteins called Src and ERK. This leads to the phosphorylation (or addition of phosphate groups) of GBF1, which in turn causes the fragmentation and disruption of the Golgi apparatus. As a result, the viral replication cycle is interrupted and the production of new virus particles is reduced or abolished.

The antiviral activity of peruvoside has been demonstrated in vitro (in cell cultures) and in vivo (in animal models) for several viruses. For example, in a mouse model of enterovirus infection, peruvoside treatment at a dose of 0.5 milligrams per kilogram of body weight resulted in 100% protection from death and complete elimination of viral load in tissues . In another study published in Antiviral Research in April 2023 , peruvoside treatment at a dose of 0.25 milligrams per kilogram of body weight significantly reduced viral load and lung damage in mice infected with SARS-CoV-2.

Peruvoside also has a low toxicity profile and minimal side effects when administered at therapeutic doses. In fact, peruvoside has been used clinically for decades as a treatment for heart failure, with no reports of serious adverse events or drug interactions . Moreover, peruvoside has a high specificity for GBF1 and does not affect other cellular proteins or functions . Therefore, peruvoside has a favorable safety margin and a low risk of resistance development.

In summary, peruvoside is a plant-derived compound that has been proven to be effective against various viruses, including SARS-CoV-2. Peruvoside works by disrupting the Golgi apparatus, which is essential for viral replication. Peruvoside has a low toxicity profile and minimal side effects when used at therapeutic doses. Peruvoside could potentially be developed as a novel antiviral drug for COVID-19 and other viral diseases.

References:

: Zhang YJ et al., Peruvoside inhibits viral replication via Src/ERK kinase cascade activation of CDK1 and GBF1 phosphorylation, Acta Pharmaceutica Sinica B (2023), https://doi.org/10.1016/j.apsb.2023.03.015.

: Chu JJ et al., Peruvoside, a cardiac glycoside, inhibits SARS-CoV-2 infection in vitro and in vivo, Antiviral Research (2023), https://doi.org/10.1016/j.antiviral.2023.105131.

: Bhatia ML et al., Haemodynamic studies with peruvoside in human congestive heart failure, British Medical Journal (1970), https://doi.org/10.1136/bmj.3.5725.740.


reference link : https://www.sciencedirect.com/science/article/pii/S2211383523001041

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