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?:abstract
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The emergence of SARS-coronavirus-2 (SARS-CoV-2) is responsible for a global pandemic disease referred to as coronavirus disease 19 (Covid-19). Hydroxychloroquine/azithromycin combination therapy is currently tested for curing Covid-19, with promising results. However, the molecular mechanism of action of this combination is not established yet. Using molecular dynamics (MD) simulations we show that both drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. We reveal unexpected molecular similarity between azithromycin and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, azithromycin interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by azithromycin and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. We also show that hydroxychloroquine molecules can saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor ACE-2. Taken together, these data show that azithromycin is directed against the virus, whereas hydroxychloroquine 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 the most efficient therapeutic intervention probably stands. This molecular mechanism may explain the beneficial effects of hydroxychloroquine/azithromycin combination therapy in patients with Covid-19. Incidentally, our data suggest that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.
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?:creator
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?:doi
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10.1016/j.ijantimicag.2020.106020
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?:doi
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?:journal
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Int_J_Antimicrob_Agents
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International_journal_of_antimicrobial_agents
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?:license
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?:pdf_json_files
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document_parses/pdf_json/8fbd2ab26d6789477da19a74381732d110b0caf5.json
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document_parses/pmc_json/PMC7219429.xml.json
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?:pmid
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?:pmid
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?:publication_isRelatedTo_Disease
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?:sha_id
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?:source
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Elsevier; Medline; PMC; WHO
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Medline
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?:title
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nSynergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal
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nSynergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: what molecular dynamics studies of virus-host interactions reveal.
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?:year
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