Graphical abstract Highlights • SARS-CoV-2 could interact with nAChRs triggering Nicotinic Cholinergic anti-inflammatory system dysregulation. • The α7 nAChRs and SARS-CoV-2 S1 interaction is significantly disturbed by the binding of AChRs agonists. • AChRs may be an intriguing therapeutic approach for the COVID-19s’ pandemic. SARS-CoV-2 infection was announced as a pandemic in March 2020. Since then, several scientists have focused on the low prevalence of smokers among hospitalized COVID-19 patients. These findings led to our hypothesis that the Nicotinic Cholinergic System (NCS) plays a crucial role in the manifestation of COVID-19 and its severe symptoms. Molecular modeling revealed that the SARS-CoV-2 Spike glycoprotein might bind to nicotinic acetylcholine receptors (nAChRs) through a cryptic epitope homologous to snake toxins, substrates well documented and known for their affinity to the nAChRs. This binding model could provide logical explanations for the acute inflammatory disorder in patients with COVID-19, which may be linked to severe dysregulation of NCS. In this study, we present a series of complexes with cholinergic agonists that can potentially prevent SARS-CoV-2 Spike glycoprotein from binding to nAChRs, avoiding dysregulation of the NCS and moderating the symptoms and clinical manifestations of COVID-19. If our hypothesis is verified by in vitro and in vivo studies, repurposing agents currently approved for smoking cessation and neurological conditions could provide the scientific community with a therapeutic option in severe COVID-19.
【저자키워드】 COVID-19, SARS-CoV-2, coronavirus, acute respiratory distress syndrome, spike glycoprotein, molecular dynamics, molecular dynamics simulations, Receptor binding domain, Severe acute respiratory syndrome, interleukin, tumor necrosis factor, Central nervous system, RBD, receptor binding domain, MD, molecular dynamics, ARDS, acute respiratory distress syndrome, IL, interleukin, SARS, Severe acute respiratory syndrome, Ligand, Acetylcholine, Middle East respiratory syndrome, MERS, Middle East respiratory syndrome, Protein Data Bank, NCBI, National Center for Biotechnology Information, ACh, Acetylcholine, AChBP, Acetylcholine-binding protein, BLAST, Basic Local Alignment Search Tool, CHARMM, Chemistry at Harvard Macromolecular Mechanics, CNS, Central Nervous System, CoV, coronavirus, DCD, single precision binary FORTRAN, ECD, extracellular domain, HADDOCK, High Ambiguity Driven protein-protein DOCKing, HMGB1, High-mobility group protein 1, Jak2, Janus kinases 2, STAT3, signal transducer and activator of transcription 3, LBD, Ligand Binding Domain, lig, ligand, MDS, Molecular Dynamics Simulations, nAChRs, nicotinic acetylcholine receptors, NAMD, Nanoscale Molecular Dynamics, NCS, Nicotinic Cholinergic System, NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells, NPT, constant number, pressure, energy, NVT, constant number, volume, energy, PDB, Protein Data Bank, PME, Particle Mesh Ewald, PRODIGY, PROtein binDIng enerGY prediction, PyMOL, Python Molecule, RMSD, Root-mean-square deviation, SARS-CoV-2 S1, SARS - 2 Spike Subunit 1 protein, STD NMR, Saturation Transfer Difference Nuclear Magnetic Resonance, TNF, Tumor Necrosis Factor, VMD, Visual Molecular Dynamics, Cholinergic agonists, Nicotinic acetylcholine receptors, AChAcetylcholine, AChBPAcetylcholine-binding protein, Acetylcholine-binding protein, ARDSacute respiratory distress syndrome, BLASTBasic Local Alignment Search Tool, Basic Local Alignment Search Tool, CHARMMChemistry at Harvard Macromolecular Mechanics, Chemistry at Harvard Macromolecular Mechanics, CNSCentral Nervous System, CoVcoronavirus, DCDsingle precision binary FORTRAN, single precision binary FORTRAN, ECDextracellular domain, extracellular domain, HADDOCKHigh Ambiguity Driven protein-protein DOCKing, High Ambiguity Driven protein-protein DOCKing, HMGB1High-mobility group protein 1, High-mobility group protein 1, ILInterleukin, Jak2Janus kinases 2, Janus kinases 2, STAT3signal transducer and activator of transcription 3, signal transducer and activator of transcription 3, LBDLigand Binding Domain, Ligand Binding Domain, ligligand, MDMolecular Dynamics, MDSMolecular Dynamics Simulations, MERSMiddle East Respiratory Syndrome, nAChRsnicotinic acetylcholine receptors, NAMDNanoscale Molecular Dynamics, Nanoscale Molecular Dynamics, NCBINational Center for Biotechnology Information, National Center for Biotechnology Information, NCSNicotinic Cholinergic System, Nicotinic Cholinergic System, NF-kBnuclear factor kappa-light-chain-enhancer of activated B cells, nuclear factor kappa-light-chain-enhancer of activated B cells, NPTconstant number, pressure, energy, constant number, NVTconstant number, volume, PDBProtein Data Bank, PMEParticle Mesh Ewald, Particle Mesh Ewald, PRODIGYPROtein binDIng enerGY prediction, PROtein binDIng enerGY prediction, PyMOLPython Molecule, Python Molecule, RBDReceptor Binding Domain, RMSDRoot-mean-square deviation, Root-mean-square deviation, SARSSevere Acute Respiratory Syndrome, SARS-CoV-2 S1SARS - 2 Spike Subunit 1 protein, SARS - 2 Spike Subunit 1 protein, STD NMRSaturation Transfer Difference Nuclear Magnetic Resonance, Saturation Transfer Difference Nuclear Magnetic Resonance, TNFTumor Necrosis Factor, VMDVisual Molecular Dynamics, Visual Molecular Dynamics, 【초록키워드】 pandemic, severe COVID-19, Anti-inflammatory, spike, SARS-COV-2 infection, Symptom, in vitro, smoking, Prevalence, Scientific community, glycoprotein, receptor, in vivo, homologous, epitope, cholinergic, binding, Interaction, Hypothesis, Therapeutic approach, Inflammatory, neurological, therapeutic option, dysregulation, clinical manifestation, smoker, Abstract, hospitalized COVID-19 patients, severe symptoms, substrate, agonist, disorder, toxins, SARS-CoV-2 S1, triggering, System, Prevent, agonists, significantly, approved, condition, complexes, patients with COVID-19, the SARS-CoV-2, 【제목키워드】 receptor, therapeutic intervention, agonist,