g(m1)-ganglioside and Coronavirus-Infections

The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme 2; Antiviral Agents; Azithromycin; Betacoronavirus; Binding Sites; Coronavirus Infections; COVID-19; Drug Synergism; G(M1) Ganglioside; Gene Expression; Host-Pathogen Interactions; Humans; Hydroxychloroquine; Kinetics; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; SARS-CoV-2; Sequence Alignment; Sequence Homology, Amino Acid; Spike Glycoprotein, Coronavirus; Thermodynamics; Virus Attachment

The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme 2; Antiviral Agents; Azithromycin; Betacoronavirus; Binding Sites; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Drug Synergism; Drug Therapy, Combination; G(M1) Ganglioside; Host-Pathogen Interactions; Humans; Hydroxychloroquine; Molecular Dynamics Simulation; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Domains; SARS-CoV-2; Sequence Alignment; Spike Glycoprotein, Coronavirus; Virus Attachment

Topics: Autoantibodies; Autoantigens; Betacoronavirus; Coronavirus Infections; COVID-19; G(M1) Ganglioside; Gangliosides; Guillain-Barre Syndrome; Humans; Male; Middle Aged; Pandemics; Pneumonia, Viral; SARS-CoV-2

The pentameric B subunit of Escherichia coli heat-labile enterotoxin (LTB) can be used as an efficient mucosal carrier of either immunogenic or tolerogenic T-cell epitopes. Co-delivery of therapeutic proteins with carrier proteins could increase the effectiveness of the antigen. This paper reports the ability of transgenic tobacco plants to express a fusion protein consisting of the synthetic LTB and a synthetic neutralizing epitope of porcine epidemic diarrhea virus (PEDV), causing an enteric disease that is especially severe in piglets. Both components of the fusion proteins were detected in Western blot analysis, and binding assay confirmed that plant-synthesized pentameric LTB-PEDV fusion bound to the intestinal membrane GM1-ganglioside receptor. This suggested that the fusion protein retained both its native antigenicity and the ability to form pentamers.

Topics: Animals; Bacterial Toxins; Base Sequence; Cloning, Molecular; Coronavirus; Coronavirus Infections; DNA Primers; Enterotoxins; Epitopes; Escherichia coli; Escherichia coli Proteins; G(M1) Ganglioside; Nicotiana; Plants, Genetically Modified; Polymerase Chain Reaction; Recombinant Fusion Proteins; Swine Diseases