BREAKING NEWS! COVID-19 Research Shows That SARS-CoV-2 Spike Proteins Also Targets Nicotine Acetycholine Receptors In Human Host, Massive Alarming Implications!

COVID-19 Research: A new study by researchers from University of Bristol-UK, University of California-San Diego and Oxford Brookes University has revealed that the spike proteins of the SARS-CoV-2 coronavirus has a high affinity for the nicotinic acetylcholine receptors (nAChRs) of human host with significant implications for pathology and infectivity of the COVID-19 disease.


 
The fact that this was overlooked from the beginning and that it took six months before this was discovered has huge implications on everything that the scientific community knows about the COVID-19 disease and the approaches towards trying to manage and treat it including drug and vaccine developments. The discovery is actually a major game changer that highlights the even growing complexity to manage and treat the COVID-19 disease and the way the SARS-CoV-2 disrupts numerous aspects of the human host body’s biological systems.
 
The research finds were just published on a preprint server and is currently being peer-reviewed. https://www.biorxiv.org/content/10.1101/2020.07.16.206680v1
 
The researchers were intrigued by the seemingly low prevalence of smokers among hospitalized patients, and it was suggested that nicotine might provide some protection in mitigating COVID-19, which was dubbed the 'protection' hypothesis.
 
Based on the early observations where smoking prevalence in hospitalized COVID-19 patients was lower than expected, certain studies suggested a role for nAChRs in the pathophysiology of COVID-19 through a direct interaction between these receptors and the viral spike glycoprotein (S-protein).
 
This hypothesis was primarily based on the fact that the S-protein from SARS-CoV-2 harbors a sequence motif related to known nAChR antagonists and may interact with nAChRs. Consequently, such interactions may be then involved in pathology and infectivity, which is a notion known as 'nicotinic hypothesis.'
 
It was also proposed that COVID-19 might be controlled or alleviated by the use of nicotine if this compound can sterically or allosterically compete with the virus for binding to nAChRs.
 
The researchers in this study used molecular simulation to examine the nicotinic hypothesis by primarily by appraising whether the SARS-CoV-2 S-protein can stably bind to nAChRs via the Y674-R685 region (i.e., a viral portion with the highest affinity to these receptors).
 
The research entailed state-of-the-art experimental procedures to explore the binding of the Y674-R685 loop of the SARS-CoV-2 S-protein to three nAChRs – namely the human α4β2 and α7 subtypes, and the muscle-like αβγδ receptor from Tetronarce californica (i.e., a species of electric ray).


Overview of the three-dimensional structures of the S protein from SARS-CoV-2 and the αβγδ nAChR from Tetron arce californica. (A) The model for the complete, fully glycosylated, SARS-CoV-2 S protein represents the closed state of the protein, after furin cleavage.17 The S protein is a homotrimer:20 each monomer is shown in a different colour, namely green, cyan and orange, with glycans depicted in pink. Each monomer is formed by three domains: head, stalk and cytoplasmic tail (CT).20 The Y674-R685 region is shown in red. In MD simulations of the glycosylated SARS-CoV-2 S protein,17 Y674-R685 is accessible, being only weakly shielded by the glycans (Figure S4) and also shows high flexibility (Figure S5). (B) The cryoEM structure of the muscle-type receptor from Tetronarce californica (PDB code: 6UWZ). 18 This receptor is a heteropentamer formed of two α (green), one β (blue), one δ (yellow), and one γ (orange) subunits. Each monomer is formed by four domains:14-16 extracellular (ECD), transmembrane (TMD), intracellular (ICD) and C-terminal domain (CTD). The agonist binding site is located in the ECDs at the interface between two neighbouring subunits.

Detailed structural models of the three SARS-CoV-2 S-peptide–nAChR complexes were constructed based on the cryo-electron microscopy structure of the αβγδ receptor with bungarotoxin. The latter is a neurotoxin that acts as a nAChR antagonist, directly competing with acetylcholine (i.e., a neurotransmitter that binds to nicotinic receptors).
 
In additions a molecular mechanics Poisson–Boltzmann surface area approach was employed to estimate the free energy of binding of the S-protein to the different receptors. This is an efficient and useful method to determine binding free energies, which is widely used to study protein-ligand interactions in medicinal chemistry and drug design.
 
Lastly, in silico alanine-scanning mutagenesis was carried out in order to pinpoint essential residues (referred by the authors to as 'hotspots') which drive all peptide-receptor associations.
 
Alarmingly, the findings reported in this study confirm and support the hypothesis that the SARS-CoV-2 S-protein can indeed interact with nAChRs.
 
Specifically, the results indicate that the Y674-R685 region from the S-protein shows a significant affinity for nAChRs in general, with the highest affinity for the nerve and muscle-like receptor.
 
Professor Dr Adrian J. Mulhollanda, corresponding author of the research, from the Centre for Computational Chemistry, School of Chemistry, University of Bristol told Thailand Medical News, "Our calculations indicate stable binding of the S-protein to these receptors through a region adjacent to the furin cleavage site and corresponding to the Y674-R685 loop. They also show apparent subtype-specific interactions, with the highest affinity for the muscle-type αβγδ receptor.”
 
It should the noted that the furin cleavage site has many implications for the viral life cycle. Additionally, the region in the S-protein that is responsible for binding to nAChRs shares high sequence similarity with neurotoxins known to be nAChRs antagonists. Thailand Medical News first highlighted this in late February .https://www.thailandmedical.news/news/breaking-latestcoronavirus-research-reveals-that-the-virus-has-mutated-gene-similar-to-hiv-and-is-1,000-times-more-potent-
 
Dr Mulhollanda explained, "Analyses of the simulations of the full-length S protein show that the Y674-R685 region is accessible for binding, and suggest a potential binding orientation of the S protein with nAChRs.”
 
Modeling studies of the interaction between the full-length S-protein and nAChRs show that association is achievable with the proteins in a non-parallel orientation to one another, which is a significant observation for further research endeavors in this field.
 
It is already known that COVID-19 can be responsible for a wide array of respiratory, muscular, clotting, heart and neurological symptoms. Hence, the interactions predicted in this study may be relevant for understanding the pathophysiology of this disease.
 
The researchers conclude, "If nicotine does indeed prove to have any clinical value, it would likely be due to interfering with the association with nAChRs.”
 
Interestingly nicotine analogs (also referred to as smoking cessation agents) –such as varenicline, cytisine, and cytisine derivatives  could also find their place in treating patients with (potentially severe) COVID-19.
 
Considering these promising results, further mutational and structural studies will be required to test the importance of SARS-CoV-2 S-protein interactions with nAChRs, with its potential relevance to pathology and infectivity of COVID-19.
 
The new findings will also change the perspective towards drug development and treatment of COVID-19 disease.
 
Thailand Medical News had already mentioned since January that the COVID-19 disease is extremely complicated and complex and that numerous factors are at play and that no single drug or single treatment protocol will be applicable to treat the disease. Rather a personalized medicine approach will be the only solution, though taxing on time and resources. We also expect new discoveries about the way the novel coronavirus attacks the human host especially in terms of long term health complications and also we will be witnessing more newer scary scenarios as the SARS-CoV-2 slowly mutates with newer strains developing and most importantly, we at Thailand Medical News warns that it is the minor mutations taking place that is often overlooked, and the resulting strains that will have the most impact on this ever growing pandemic.
 
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