Nicotinic cholinergic system and COVID-19: In silico identification of interactions between α7 nicotinic acetylcholine receptor and the cryptic epitopes of SARS-Co-V and SARS-CoV-2 Spike glycoproteins

Lagoumintzis, George; Chasapis, Christos T.; Alexandris, Nikolaos; Kouretas, Demetrios; Tzartos, Socrates J.; Eliopoulos, Elias; Farsalinos, Konstantinos; Poulas, Konstantinos

doi:10.1016/j.fct.2021.112009

Cited by 50 publications

(54 citation statements)

References 94 publications

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“…Farsalinos et al have identified a “toxin-like” amino acid in the receptor binding domain of the spike glycoprotein of SARS-CoV-2, that is homologous to a sequence found in snake venom known to interact with nicotinic acetylcholine receptors (nAChRs). 20,21 Further, binding simulation studies have shown that SARS-CoV-2 has the ability to directly bind to nAChRs via its spike protein. 22 Binding to the nAChRs may explain the immune-mediated flares or myasthenia gravis-like findings in patients with autoimmune disease infected with SARS-CoV-2, or those vaccinated with mRNA/DNA based vaccines.…”

Section: Introductionmentioning

confidence: 99%

Varenicline Prevents SARS-CoV-2 Infection In Vitro and in Rhesus Macaques

Nau¹,

Luthra

Lanzer

et al. 2021

Preprint

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Background SARS-CoV-2 infections have resulted in a global pandemic, but an antiviral therapy for this novel strain of coronavirus does not currently exist. The objective of our study was to investigate the antiviral potential of the nicotinic acetylcholine receptor (nACHR) agonist varenicline tartrate against SARS-CoV-2. Methods We assessed antiviral activity using in vitro human cell assays and we assessed in vivo efficacy in a rhesus macaque model. Results In vitro studies found that varenicline tartrate, over a range of concentrations, reduced the infectivity of SARS-CoV-2 wildtype, alpha, and beta variants in Calu-3 cells and Caco-2 cells, with maintenance of cell viability. In vivo studies found that varenicline tartrate, administered as a nasal spray to rhesus macaques, reduced SARS-CoV-2 wildtype viral load and inhibited viral replication in the nasal mucosa and upper airway. Conclusion Although the study reported here was exploratory, we have confirmed that the nAChR agonist varenicline has the potential to interact with and inhibit SARS-CoV-2 infection and replication.

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Section: Introductionmentioning

confidence: 99%

Varenicline Prevents SARS-CoV-2 Infection In Vitro and in Rhesus Macaques

Nau¹,

Luthra

Lanzer

et al. 2021

Preprint

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“…The target-finding is based on molecular similarities only, without there being any bias toward molecules of relevance to SARS-COV-2. One of the targets found was nicotinic acetylcholine receptor, which was recently reported to be involved in the pathophysiology of SARS-COV-2 [ 14 , 15 ]⁠. Our results show that HCQ binds directly to α7 nicotinic acetylcholine (α7 nAChR) and ACE2 receptors [ 3 ] in a way that would interfere with the binding of the viral spike protein to these receptors⁠.…”

Section: Introductionmentioning

confidence: 70%

“…Only those targets that gave a docking score of −8 kcal/mol or better ( Table 2 a), were pursued further, and these targets are: ACE2, α7 nAChR, α1D-AR, DNA gyrase and HNMT ( Table 2 a). Among the two types of acetylcholine receptors, nAChR was relevant to SARS-COV-2 infection and hence it was taken-up for our studies [ 14 , 15 ]. Many other targets that have given good docking scores with HCQ are found to be directly relevant to SARS-COV-2 infection [ 5 , 13 ]⁠.…”

Section: Resultsmentioning

confidence: 99%

“…Binding of HCQ to ACE2 has the potential to affect viral spike protein binding in two ways: 1) by affecting the glycosylation of ACE2 and 2) by blocking the spike protein binding site on ACE2 [ 44 ]. Interestingly, an equally high docking score is obtained for the target α7 nAChR, which has only recently been shown to be involved in the pathophysiology of SARS-COV-2 [ 14 , 15 ]⁠. The high score for the adrenergic receptor, which is part of the cholinergic pathway, is significant because recently α1D-AR antagonists are found to reduce mortality in COVID-19 patients, and HCQ binding can affect catecholamine signaling pathways during inflammatory cytokine production that is linked to many deaths [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

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A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

Navya

Hosur

2021

Informatics in Medicine Unlocked

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COVID-19 disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has posed a global health emergency. Repurposing of existing drugs can be a rapid and effective strategy to fight the infection. Clinical trials have reported reduction or elimination of viral load when patients were treated with the anti-malarial drug Hydroxychloroquine (HCQ). To understand the molecular mechanism of action for effective repurposing of this drug we have carried out in silico docking and dynamics studies on complexes between HCQ and target proteins, which were identified through both literature survey and structural similarity searches in databases of small molecule – protein complexes. The proteins identified as binding HCQ are: Angiotensin Converting Enzyme 2 (ACE2), α7 nicotinic AcetylCholine Receptor (α7 nAChR), α1D-adrenergic receptor (α1D-AR), Histamine N- Methyl Transferase (HNMT) and DNA gyrase/Topoisomerase III β (Top3β). The majority of these proteins are novel and have not been used before, in docking studies. Our docking and simulation results support action of HCQ both at the entry and post-entry stages of SARS-CoV2 infection. The mechanism of action at the entry stage is through blocking the virus-binding sites on the two receptors, ACE2 & α7 nAChR, by binding directly at those sites. Our computational studies also show that the action of HCQ at the post-entry stage is to prevent both viral replication and generation of ‘cytokine storm’ by inhibiting host Top3β enzyme and α1D-AR, respectively. Binding of HCQ to HNMT is not a desired binding, and therefore this should be reduced during repurposing of HCQ.

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“…A further argument to suggest that nicotinic receptor stimulation could be beneficial in COVID-19 is that it could counteract the inhibitory effect of SARS-CoV2 on nicotinic receptors. As a matter of fact, it has been observed the S protein of SARS CoV2 shows sequence analogies with the nAChR blocker α-bungarotoxin ( Kimura et al, 2019 ), and in silico studies showed that it can bind to nAChR and that several nAChR agonists including nicotine can effectively prevent this binding ( Alexandris et al, 2020 ; Lagoumintzis et al, 2021 ). The inhibitory effects of SARS-CoV2 on nAChR are expected to imbalance the equilibrium between Ang II and Ang-(1-7) in favor of the former, hence promoting lung inflammation, whereas cholinergic stimulation could bring back to normal the Ang II/Ang-(1-7) balance.…”

Section: Does the Cholinergic Anti-inflammatory Pathway Regulate Pulmonary Ras Hints From The Covid-19 Pandemics?mentioning

confidence: 99%

The Cholinergic and ACE-2-Dependent Anti-Inflammatory Systems in the Lung: New Scenarios Emerging From COVID-19

et al. 2021

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The renin angiotensin system and the cholinergic anti-inflammatory pathway have been recently shown to modulate lung inflammation in patients with COVID-19. We will show how studies performed on this disease are starting to provide evidence that these two anti-inflammatory systems may functionally interact with each other, a mechanism that could have a more general physiological relevance than only COVID-19 infection.

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Nicotinic cholinergic system and COVID-19: In silico identification of interactions between α7 nicotinic acetylcholine receptor and the cryptic epitopes of SARS-Co-V and SARS-CoV-2 Spike glycoproteins

Cited by 50 publications

References 94 publications

Varenicline Prevents SARS-CoV-2 Infection In Vitro and in Rhesus Macaques

Varenicline Prevents SARS-CoV-2 Infection In Vitro and in Rhesus Macaques

A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

The Cholinergic and ACE-2-Dependent Anti-Inflammatory Systems in the Lung: New Scenarios Emerging From COVID-19

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