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Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal.
Int J Antimicrob Agents. 2020 Aug; 56(2):106020.IJ

Abstract

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.

Authors+Show Affiliations

INSERM UMR_S 1072, 13015 Marseille, France.Aix-Marseille Université, 13015 Marseille, France.Aix-Marseille Université, 13015 Marseille, France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32405156

Citation

Fantini, Jacques, et al. "Synergistic Antiviral Effect of Hydroxychloroquine and Azithromycin in Combination Against SARS-CoV-2: what Molecular Dynamics Studies of Virus-host Interactions Reveal." International Journal of Antimicrobial Agents, vol. 56, no. 2, 2020, p. 106020.
Fantini J, Chahinian H, Yahi N. Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal. Int J Antimicrob Agents. 2020;56(2):106020.
Fantini, J., Chahinian, H., & Yahi, N. (2020). Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal. International Journal of Antimicrobial Agents, 56(2), 106020. https://doi.org/10.1016/j.ijantimicag.2020.106020
Fantini J, Chahinian H, Yahi N. Synergistic Antiviral Effect of Hydroxychloroquine and Azithromycin in Combination Against SARS-CoV-2: what Molecular Dynamics Studies of Virus-host Interactions Reveal. Int J Antimicrob Agents. 2020;56(2):106020. PubMed PMID: 32405156.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal. AU - Fantini,Jacques, AU - Chahinian,Henri, AU - Yahi,Nouara, Y1 - 2020/05/13/ PY - 2020/04/03/received PY - 2020/05/04/accepted PY - 2020/5/15/pubmed PY - 2020/9/2/medline PY - 2020/5/15/entrez KW - ACE-2, angiotensin-converting enzyme-2 KW - ATM, azithromycin KW - Azithromycin KW - CLQ, chloroquine KW - CLQ-OH, hydroxychloroquine KW - COVID-19, coronavirus disease 19 KW - Chloroquine KW - Coronavirus KW - Ganglioside KW - NTD, N-terminal domain KW - Pandemic KW - RBD, receptor binding domain KW - SARS-CoV, severe acute respiratory syndrome coronavirus KW - SARS-CoV-2 KW - SARS-CoV-2, SARS-coronavirus-2 SP - 106020 EP - 106020 JF - International journal of antimicrobial agents JO - Int. J. Antimicrob. Agents VL - 56 IS - 2 N2 - 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. SN - 1872-7913 UR - https://www.unboundmedicine.com/medline/citation/32405156/Synergistic_antiviral_effect_of_hydroxychloroquine_and_azithromycin_in_combination_against_SARS_CoV_2:_What_molecular_dynamics_studies_of_virus_host_interactions_reveal_ L2 - https://linkinghub.elsevier.com/retrieve/pii/106020 DB - PRIME DP - Unbound Medicine ER -