Austrian Study Shows Calcium Channel Inhibitors Including Amlodipine, Nifedipine, Felodipine And The Phytochemical Neferine Can Treat COVID-19 Infections

Calcium Channel Inhibitors-SARS-CoV-2: A new study by researchers from the Institute of Biophysics, Johannes Kepler University Linz-Austria has found that calcium channel inhibitors including existing drugs such as amlodipine, nifedipine, felodipine, verapamil and the phytochemical neferine from the lotus plants can possibly treat SARS-CoV-2 infections.

Strategies for inhibition of cellular calcium transport systems involved in viral infection cascades. Calcium levels dictate the activity of the NLRP3 inflammasome, eventually leading to pyroptosis of the cell. CCBs have been shown to interact with TRP, L-type Ca2+ channels as well as ACE2 and thus have the potential to inhibit SARS-CoV-2 endocytosis. Auxora is a specific inhibitor of the STIM/Orai system, which has been implicated in inflammation-induced injury of pulmonary endothelial cells as well as proinflammatory cytokine storms that contribute to severe COVID-19 disease. There is evidence that TRPML2 channels have a role in the endocytosis of SARS-CoV-2 into host cells. Potential drugs designed for these channels could be strong tools in the treatment of COVID-19.

The SARS-CoV-2 coronavirus is a positive-sense single-stranded RNA virus that causes the COVID-19 disease. Global research effort has considerably increased humanity’s knowledge about both viruses and disease. It has also spawned several vaccines that have proven to be key tools in attenuating the spread of the pandemic and severity of COVID-19.

However, with vaccine-related skepticism being on the rise, as well as breakthrough infections in the vaccinated population, the repeated overstrain placed by high numbers of hospitalizations and the horrifying numbers of deaths on healthcare facilities and workers indicates the urgent need to develop other effective measures to deal with the mounting waves of cases driven by the emergence of successive variants of the virus, with higher transmissibility and immune escape characteristics.
 
Calcium signals have long been known to play an essential role in infection with diverse viruses and thus constitute a promising avenue for further research on therapeutic strategies.
 
The Calcium Channel Inhibitors-SARS-CoV-2 study team in a research review introduced the pivotal role of calcium signaling in viral infection cascades. Based on this, the study team presents prospective calcium-related treatment targets and strategies for the cure of COVID-19 that exploit viral dependence on calcium signals.
 
The study findings were published in the peer reviewed journal: Cells.
https://www.mdpi.com/2073-4409/11/2/253/htm
 
The study findings discuss the role of calcium signaling pathways as targets of inhibition in potential new antiviral therapeutic pathways.
 
Typically, calcium is involved in multiple essential physiological pathways, and is known as the second messenger, mediating the transmission of the signal from one excitable tissue to another via a chemical chain, as well as being the trigger for several cascading pathways. This is seen, for instance, in muscle contraction, cell signaling, and t he immune response.
 
Along with the central place of calcium in bodily processes, the concentrations of calcium within the cell and within cell organelle compartments are maintained within very tight limits, using various energy-intensive methods including molecular pumps, ion channels and ATPases.
 
However, it has been found that calcium ion movement is disrupted severely during viral infections, as the infectious particle hijacks cell signaling pathways to replicate itself within the infected cell.
 
This has been found within coronaviruses too as the viral envelope proteins have been found to act as calcium ion channels within key protein processing organelles like the endoplasmic reticulum Golgi apparatus intermediate compartment (ERGIC). This disruption results in the activation of inflammasomes of the NLRP3 type.
 
NLRP3 type inflammasomes are protein oligomers, the formation of which is triggered by the presence of pathogen-associated molecular patterns (PAMP). These complexes form receptors that activate caspase-dependent cytokine pathways that cause pyroptosis.
 
It has been found that with the SARS-CoV-2 virus too, calcium-binding is considered to promote virus-host cell interactions. For instance, calcium signaling pathways have also been considered therapeutic pathways.
 
In the past, calcium channel blockers were successfully tested against flu viruses, the Japanese encephalitis virus, and the Ebola virus, among others.
 
This study explores the potential for the use of calcium inhibitors in SARS-CoV-2 infections.
 
Basically, the entry of calcium into the cells occurs via several types of calcium channels.
 
The first type, voltage-gated calcium ion channels are found mostly in the cell membrane of excitable cells. Membrane depolarization causes the rapid influx of calcium, shifting the membrane potential towards the positive side. These are the channels allowing for the fastest movement of calcium ions in the cytosol and are thus found in excitable tissues, including pacemaker, neuronal or certain types of cardiac cells, as well as skeletal muscle cells.
 
These channels mediate hormone secretion, heart contraction, visual signals and neurotransmitter release, and are targeted in the treatment of several diseases. Several inhibitors of these channels, such as amlodipine, nifedipine, felodipine, verapamil and diltiazem are being tested for the current infection as well.
 
However, among these, nifedipine and felodipine have highly selective activity, while the former, along with amlodipine, also reduces the risk of death and intubation among the elderly with severe COVID-19.
 
This might be due to smooth muscle relaxation of the pulmonary vasculature, improving hypoxia. Treatment with calcium channel blockers was associated with an anti-inflammatory effect and thus a reduced likelihood of cytokine storm.
 
Interestingly, a new plant-derived natural phytochemical, called neferine, was also identified as a potential entry inhibitor of the virus, and showed 75% inhibition of infection in cell cultures in a pseudovirus assay, by inhibiting calcium channels in the cell membrane. https://pubmed.ncbi.nlm.nih.gov/34061377/
 
Neferine is a major active component isolated from green seedlings of Nelumbo nucifera Gaerth (Lotus) which have been consumed as a staple food and are used in traditional Chinese medicine. The other pharmacological activities of neferine include antihypertensive, antiarrhythmic, anti-cancer, anti-diabetic, anti-aging, anti-microbial, anti-thrombotic, anti-inflammatory, anti-HIV, sedative and cholinesterase inhibitory actions.
 
Neferine could attenuate bleomycin-induced pulmonary fibrosis as well. https://pubmed.ncbi.nlm.nih.gov/19909737/
 
Neferrine is also one of the key components of TMN’s latest updated version of prophylatic and therapeutic teas. https://www.thailandmedical.news/news/new-therapeutic-teas-
 
The second type ie store-operated channels open when intracellular endoplasmic reticulum (ER) calcium stores are depleted, producing a Ca2+-selective CRAC current (ICRAC). The effect is phospholipase C (PLC) activation, with subsequent release of cytosolic inositol trisphosphate (IP3), and the exit of calcium along the IP3 receptors. This leads to CRAC channel activation.

CRAC channels regulate calcium channels in multiple cells including T cells, where they are activated by T cell receptor (TCR) stimulation. Anomalies in this pathway lead to the occurrence of severe combined immunodeficiency (SCID) following single point mutations at strategic sites. The T cells formed in such patients show reduced proliferative and functional activity following antigen exposure, resulting in chronic and recurrent viral infections.
 
Hence CRAC channels are involved in the cytotoxic T cell activity against viruses. These cells also provide durable protection against reinfection via memory T cell generation and maintenance, in collaboration with T helper cells. Memory T cells are part of a robust adaptive cellular immune response, expanding rapidly on exposure to the same virus or a secondary virus and then forming effector T cells that eliminate the infected cells. 
 
It should be noted that CRAC channels are also important to antigen-TCR interaction that results in T cell activation, which supports the presence of a positive feedback loop between the TCR-increased calcium signaling following repeated antigen exposure-T cell activation.
 
Besides this obvious role in antiviral immunity, CRAC channels may also be involved in the hyperinflammatory injury to lung endothelium, and the cytokine storm, seen in some patients following SARS-CoV-2 infection.
 
With the knockout of a key protein in this process, the STIM1 protein, the cell displayed high interferon-1 responses that led to robust resistance to the virus. conversely, the knockout of the Orai1 gene led to ready infection with the virus due to the lowered expression of calcium-dependent transcription factors that encode antiviral molecules.
 
A variety of CRAC channel inhibitors could be useful in treating cases of severe COVID-19. A novel nanoemulsion formulation of CM4620, named Auxora, is now in phase 2 trials for acute pancreatitis treatment. However, in such conditions, it inhibits inflammation in the lung caused by calcium influx, simultaneously lowering cytokine-mediated inflammation.
 
Interestingly encouraging reductions in recovery time were observed in severe COVID-19 pneumonia when treated with Auxora vs standard of care, with similar reductions in the proportion that required intubation. This agent may protect the lung endothelium and also suppress the spike in inflammatory cytokine production. https://link.springer.com/article/10.1186/s13054-020-03220-x
 
The other auxiliary proteins that could regulate the CRAC channel traffic include the chaperone heat shock protein 27 (HSP27) that promotes STIM1 expression. HSP27 vaccines are being considered as a potential agent to prevent severe COVID-1-associated inflammation, promote endothelial repair and regrowth, and increase the production of white cells.
 
Cav-1 (Caveolin-1) is another multifunctional calcium channel auxiliary protein, with multiple binding sites on SARS-CoV-2. However, its absence on placental syncytiotrophoblast may explain the lack of vertical transmission of the virus in pregnant women.
 
The third type ie transient receptor potential (TRP) channels form a large family, of which especially TRPV5 and TRPV6 selectively transport calcium ions. The expression of TRP channels in virally infected tissues may be linked to viral entry, trafficking within the endosomes to promote viral entry, and the systemic response to the infection. These, therefore, provide a favorable environment for viruses, and they contribute largely to the calcium signaling system in infected hosts.
 
Interesting Nigella Sativa or Black cumin has been reported to reduce COVID-19 symptom severity and clear the virus, when given over two weeks, possibly due to the presence of thymoquinone, and possibly involving TRP channel suppression. https://www.thailandmedical.news/news/breaking-university-of-technology-sydney-confirms-that-the-phytochemical-thymoquinone-found-in-nigella-sativa-is-able-to-treat-covid-19
 
https://www.thailandmedical.news/news/covid-19-herbs-multicenter-randomized-controlled-trial-shows-that-nigella-sativa-and-honey-is-able-to-treat-moderate-to-severe-covid-19-patients
 
https://biomedres.us/fulltexts/BJSTR.MS.ID.005552.php
 
https://pubmed.ncbi.nlm.nih.gov/33976534/
 
Nigella Sativa or Black cumin is also one of the components of TMN’s latest updated version of prophylatic and therapeutic teas. https://www.thailandmedical.news/news/new-therapeutic-teas-
 
https://www.thailandmedical.news/news/updates-on-tmn-prophylactic-and-therapeutic-teas
 
The other potential candidates include cannabidiol (CBD) from cannabis, which uses several TRP channels as its receptors, as well as berbamine, resveratrol, quercetin, and curcumin, among others. Spices like ginger, hot peppers, turmeric and pepper, as well as onions, contain anti-inflammatory compounds that interact with these channels as well. Read Also: https://www.thailandmedical.news/articles/covid-19-herbs
 
The study findings showed that the use of calcium channel blockers may be helpful in treating SARS-CoV-2 infection by preventing pathological changes in the infected cell, mediated by calcium ions. Calcium trafficking within the infected cell is a subject worthy of further study, and its inhibition may thus be a valuable method to target the virus at different levels, exploiting the various types of calcium channels.
 
However, the inhibition of such channels must also take into account the many and diverse off-target effects, such as those following upon CRAC channel inhibition, since these are found throughout the host organism. Complete CRAC inhibition is therefore not required, in all probability, to achieve antiviral efficacy.
 
The study team say that further detailed exploration of target and side effects will need to be carried out to elucidate the value of calcium channel inhibitors, as well as therapeutic hypocalcemia or calcium supplementation.
 
The study tea concluded that overall, given the multitude of indications that CCBs (calcium channel blockers) may contribute to a better outcome of COVID-19 disease, it might be worthwhile to focus research in this direction while keeping an eye on the future endemic state of SARS-CoV-2.
 
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