Abstract
While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine other potential interactions between the virus and other cell receptors. Based on the clinical observation of low prevalence of smoking among hospitalized COVID-19 patients, we examined and identified a “toxin-like” amino acid (aa) sequence in the Receptor Binding Domain of the Spike Glycoprotein of SARS-CoV-2 (aa 375–390), which is homologous to a sequence of the Neurotoxin homolog NL1, one of the many snake venom toxins that are known to interact with nicotinic acetylcholine receptors (nAChRs). We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein and the superposition of the modelled structure of the Neurotoxin homolog NL1 and the SARS-CoV-2 Spike Glycoprotein. We also performed computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 Spike Glycoprotein and the extracellular domain of the nAChR α9 subunit. We identified a main interaction between the aa 381–386 of the SARS-CoV-2 Spike Glycoprotein and the aa 189–192 of the extracellular domain of the nAChR α9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the α9 nAChR and α-bungarotoxin. A similar interaction was observed between the pentameric α7 AChR chimera and SARS-CoV-2 Spike Glycoprotein. The findings raise the possibility that SARS-CoV-2 may interact with nAChRs, supporting the hypothesis of dysregulation of the nicotinic cholinergic system being implicated in the pathophysiology of COVID-19. Nicotine and other nicotinic cholinergic agonists may protect nAChRs and thus have therapeutic value in COVID-19 patients.
Highlights
As the global pandemic of corona virus disease 2019 (COVID-19) was spreading, it was recognized early that the virus (SARS-COV-2) uses the angiotensin converting enzyme 2 (ACE2) as a receptor for cell entry [1]
Considering the above, we focused on the potential interaction between SARS-CoV-2 and the nicotinic cholinergic system, α7 nicotinic acetylcholine receptors (nAChRs) [10]
The identification of a potential interaction between any virus protein and the cholinergic pathway could promote a better understanding of the large spectrum of COVID-19 clinical manifestations and could lead to the identification of potentially therapeutic compounds among the many cholinergic agonists. Such interactions could explain the previously mentioned clinical observations of under-representation of smokers among hospitalized COVID-19 patients. This would establish the hypothesis that SARS-CoV-2 disrupts the cholinergic anti-inflammatory pathway and causes a variety of clinical manifestations by interacting with nAChRs, and nicotine could prevent this by restoring the function of these receptors
Summary
As the global pandemic of corona virus disease 2019 (COVID-19) was spreading, it was recognized early that the virus (SARS-COV-2) uses the angiotensin converting enzyme 2 (ACE2) as a receptor for cell entry [1]. The identification of a potential interaction between any virus protein and the cholinergic pathway could promote a better understanding of the large spectrum of COVID-19 clinical manifestations and could lead to the identification of potentially therapeutic compounds among the many cholinergic agonists Such interactions could explain the previously mentioned clinical observations of under-representation of smokers among hospitalized COVID-19 patients. This would establish the hypothesis that SARS-CoV-2 disrupts the cholinergic anti-inflammatory pathway and causes a variety of clinical manifestations by interacting with nAChRs, and nicotine could prevent this by restoring the function of these receptors. We present the hypothesis that nicotine and other nicotinic cholinergic agonists may have a therapeutic value in COVID-19
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