g(m1)-ganglioside and Pneumonia--Viral

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 role of natural killer (NK) cells in host defenses against influenza virus infections in the lung was investigated by using rabbit antiserum to asialo GM1 (RAGM1), a neutral glycosphingolipid expressed on the plasma membrane of NK cells and some mouse pulmonary macrophages. Intravenous or intratracheal (i.t.) administration of RAGM1 resulted in depletion of the (in vitro) NK activity in lung and spleen or lung alone, respectively. The NK activity was depleted as early as 12 hr post-inoculation of antiserum, but returned to the normal range of activity by 4 days after antibody administration. RAGM1 serum treatment had no effect on the cytotoxic macrophage activity expressed by the plastic-adherent mononuclear cell populations isolated from mouse or hamster lung. Treatment of mice or hamsters with an i.t. or i.v. inoculation of RAGM1 rendered both species of laboratory animals susceptible to increased morbidity and mortality during a pulmonary influenza infection. These data support the hypothesis that a population of NK cells exist in an extravascular compartment within the lung, and that this local population of NK cells in the lung is crucial to the early natural pulmonary defenses during influenza infection.

Topics: Animals; Cricetinae; Cytotoxicity, Immunologic; Female; G(M1) Ganglioside; Glycosphingolipids; Immune Sera; Immunity, Innate; Immunization, Passive; Influenza A virus; Killer Cells, Natural; Macrophages; Mice; Mice, Inbred Strains; Orthomyxoviridae Infections; Pneumonia, Viral; Rabbits; Species Specificity