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.

Links

Publisher Full Text
ncbi.nlm.nih.gov
linkinghub.elsevier.com
PMC Free PDF
Aggregator Full Text

Authors+Show Affiliations

Fantini J
INSERM UMR_S 1072, 13015 Marseille, France.
Chahinian H
Aix-Marseille Université, 13015 Marseille, France.
Yahi N
Aix-Marseille Université, 13015 Marseille, France.

MeSH

Amino Acid SequenceAngiotensin-Converting Enzyme 2Antiviral AgentsAzithromycinBetacoronavirusBinding SitesCOVID-19Coronavirus InfectionsDrug SynergismG(M1) GangliosideGene ExpressionHost-Pathogen InteractionsHumansHydroxychloroquineKineticsMolecular Docking SimulationMolecular Dynamics SimulationPandemicsPeptidyl-Dipeptidase APneumonia, ViralProtein BindingProtein Conformation, alpha-HelicalProtein Conformation, beta-StrandProtein Interaction Domains and MotifsSARS-CoV-2Sequence AlignmentSequence Homology, Amino AcidSpike Glycoprotein, CoronavirusThermodynamicsVirus Attachment

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32405156