COVID-19 and Cholinergic Anti-inflammatory Pathway:In silicoIdentification of an Interaction between α7 Nicotinic Acetylcholine Receptor and the Cryptic Epitopes of SARS-CoV and SARS-CoV-2 Spike Glycoproteins

Abstract

SARS-CoV-2 is the coronavirus that originated in Wuhan in December 2019 and has spread globally. The observation of a low prevalence of smokers among hospitalized COVID-19 patients has led to the development of a hypothesis that nicotine could have protective effects by enhancing the cholinergic anti-inflammatory pathway. Based on clinical data and on modelling and docking experiments we have previously presented the potential interaction between SARS-CoV-2 Spike glycoprotein and nicotinic acetylcholine receptors (nAChRs), due to a "toxin-like" epitope on the Spike Glycoprotein, with homology to a sequence of a snake venom toxin. We here present that this epitope coincides with the well-described cryptic epitope for the human antibody CR3022 and with the epitope for the recently described COVA1-16 antibody. Both antibodies are recognizing neighboring epitopes, are not interfering with the ACE2 protein and are not able to inhibit SARS-CoV and SARS-CoV-2 infections. In this study we present the molecular complexes of both SARS-CoV and SARS-CoV-2 Spike Glycoproteins, at their open or closed conformations, with the molecular model of the human α7 nAChR. We found that the interface of all studied protein complexes involves a large part of the "toxin-like" sequences of SARS-CoV and SARS-CoV-2 Spike glycoproteins and toxin binding site of human α7 nAChR.

Nicotinic cholinergic system and COVID-19: In silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions

“…2 . As we have previously reported [[ 36 ] Preprint], α7 nAChRs appear to possess a LBD that could harbor toxin-like sequences identified in the Receptor Binding Domain (RBD) of the SARS-CoV and SARS-CoV-2 Spike glycoproteins (A7J8L4, P0DTC2). This specific LBD comprises residues preserved in the binding site of nAChRs and shows homology across the AChBP sequences that bind the agonists, as mentioned earlier.…”

“…We have previously described the molecular complexes of human α7 nAChR to both SARS-CoV and SARS-CoV-2 Spike glycoproteins, either in their open or closed conformation [[ 36 ], preprint]. We have observed that a significant portion of the "toxin-like" sequence in SARS-CoV and SARS-CoV-2 Spike can interact with the toxin binding sites of human α7 nAChR in the nM range, which is comparable with experimental supported Kds of well-known enzymatic interacting partners that produce stable protein complexes [ 56 ].…”

“…Sequence retrieval and alignment between SARS-CoV's Spike glycoproteins have been previously shown by our group [ 35 , 36 ]. Likewise, sequence alignment (of nAChRs, AChBP, and coordinating residues of cholinergic agonists studied) was performed using the National Center for Biotechnology Information databases (USA), the Mega BLAST with the UniProt protein database, and the BLASTP (protein-protein BLAST) with default parameters.…”

“…In this context, we recently suggested that the NCS might be involved in the pathophysiology of COVID-19. We also extended this hypothesis by studying in silico molecular interactions between the human neuronal α7 and the spike glycoprotein of SARS-CoV-2 [ 35 , 36 ]. Expanding our previously published work, we present the in silico molecular interactions of the protein complexes between the homologous to the extracellular domain (ECD) of the human α7 AChR, the acetylcholine binding protein (AChBP) bound to the most known nAChRs' agonists, and the SARS-CoV-2 Spike glycoprotein.…”

Cholinergic and lipid mediators crosstalk in Covid-19 and the impact of glucocorticoid therapy

“…preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.07. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.07.20248970 doi: medRxiv preprint acetylcholine receptor, which may compromise the cholinergic anti-inflammatory pathway 111 .…”