Calcium Channel Inhibitors Can Treat COVID-19 Infections

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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.

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

Since vaccines became widely available at the end of 2020, many countries have been struggling to immunize sufficient proportions of their population to contain further viral spread. Recurrent waves of infection paired with more infectious virus variants are still placing a severe strain on public health systems, preventing governments from abolishing safety regulations and returning their countries to a pre-pandemic state.

Potential explanations for recurrent infection waves include mutations of the virus that lead to (partial) evasion of vaccine-derived antibodies, anti-vaccination movements spreading misinformation, unsubstantiated rejection/fear of COVID-19 vaccines, conspiracy theories as well as mistrust in pharmaceutical companies or public institutions [12,13,14,15,16,17].

Aside from countering these obstacles, effective post-infection treatments are required to finally put a stop to the overload of hospitals, particularly intensive care units (ICUs).

Calcium (Ca2+) as an important second messenger in excitable and non-excitable cells controls essential functions such as muscle contraction, cellular signaling processes and immune responses [18]. Intracellular and organellar calcium concentrations are tightly controlled via various pumps, ATPases, ion channels and uniporters, which have been increasingly studied over the past years. During viral infection, cellular calcium dynamics are highly affected as dysregulation of host cell signaling cascades is elicited by these infectious agents [19].

The role of calcium in virus-host cell interaction has been proven for various types of viruses, including coronaviruses. For instance, in a study from 2015, Nieto-Torres et al., discovered that the coronavirus envelope (E) protein of SARS-CoV activates the so-called NLR family pyrin domain containing 3 (NLRP3) inflammasome by functioning as a Ca2+ channel in endoplasmic reticulum Golgi apparatus intermediate compartment (ERGIC) as well as Golgi membranes [20].

Inflammasomes are protein complexes that oligomerize and form receptors upon the detection of pathogen-associated molecular pattern (PAMP) signals in host cells, activating caspases that produce cytokines and initiate pyroptotic cell death [21].

Importantly, the inflammatory signaling cascade that leads to the activation of the NLRP3 inflammasome, regulated by interleukin 1 beta (IL-1β), mainly depends on Ca2+ levels [22,23].

Due to these findings, calcium has also been considered an important factor during SARS-CoV-2 infection. Recently, Khelashvili and co-workers proposed the potential binding of calcium to six acidic residues located at the fusion protein (FP) of the SARS-CoV-2 spike protein (E819, D820, D830, D839, D843, and D848), which modulates the ability of the virus to insert into lipid membranes. Using molecular dynamics (MD) simulations they suggested that the binding of calcium enhances the interactions between the fusion peptide and the host cell membrane [24,25,26,27]. For another review on the role of Ca2+ during infection see [28].

Due to the importance of calcium in viral infections, several calcium entry and cellular signaling pathways are considered as feasible drug target sites. In this regard, the use of inhibitors specific for calcium ion channels was successfully proven to be effective against influenza A virus, Japanese encephalitis virus (JEV), hemorrhagic fever arenavirus (NWA), or ebolavirus [27,29,30,31,32].

Based on these results, this review addresses the potential positive effects of calcium-related treatment targets and strategies to modulate calcium entry and cellular signaling pathways on the outcome of SARS-CoV-2 infections and COVID-19.

Cells 11 00253 g001
Figure 1. 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. CBD decreases expression of ACE2 and TMPRSS2, which are both integral players in SARS-CoV-2 infection. Double-membrane vesicles (DMVs) are derived from ER membranes and formed by non-structural proteins (NSPs) 3–6 to facilitate viral RNA replication in separate compartments, as it would be impaired by immune-responses in the cytosol. HSP27 vaccination might attenuate inflammation and increase tissue regeneration. Inhibition of ERp57 might impair correct spike-folding during virus replication. Knockout/knockdown of the Sigma-1 receptor has been shown to reduce viral replication, Numbers in bubbles denote sections describing the indicated proteins and mechanisms in detail.

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