CovidFranceV1, Main, Exploration, bibRecord, 000535

Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal.

Identifieur interne : 000535 ( Main/Exploration ); précédent : 000534; suivant : 000536

Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal.

Auteurs : Jacques Fantini [France] ; Henri Chahinian [France] ; Nouara Yahi [France]

Source :

International journal of antimicrobial agents [ 1872-7913 ] ; 2020.

RBID : pubmed:32405156

Descripteurs français

English descriptors

KwdEn :
- Amino Acid Sequence (MeSH), Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Azithromycin (chemistry), Azithromycin (pharmacology), Betacoronavirus (drug effects), Betacoronavirus (growth & development), Betacoronavirus (metabolism), Binding Sites (MeSH), Coronavirus Infections (drug therapy), Coronavirus Infections (virology), Drug Synergism (MeSH), G(M1) Ganglioside (antagonists & inhibitors), G(M1) Ganglioside (chemistry), G(M1) Ganglioside (metabolism), Gene Expression (MeSH), Host-Pathogen Interactions (drug effects), Host-Pathogen Interactions (genetics), Host-Pathogen Interactions (immunology), Humans (MeSH), Hydroxychloroquine (chemistry), Hydroxychloroquine (pharmacology), Kinetics (MeSH), Molecular Docking Simulation (MeSH), Molecular Dynamics Simulation (MeSH), Pandemics (MeSH), Peptidyl-Dipeptidase A (chemistry), Peptidyl-Dipeptidase A (genetics), Peptidyl-Dipeptidase A (metabolism), Pneumonia, Viral (drug therapy), Pneumonia, Viral (virology), Protein Binding (MeSH), Protein Conformation, alpha-Helical (MeSH), Protein Conformation, beta-Strand (MeSH), Protein Interaction Domains and Motifs (MeSH), Sequence Alignment (MeSH), Sequence Homology, Amino Acid (MeSH), Spike Glycoprotein, Coronavirus (antagonists & inhibitors), Spike Glycoprotein, Coronavirus (chemistry), Spike Glycoprotein, Coronavirus (genetics), Spike Glycoprotein, Coronavirus (metabolism), Thermodynamics (MeSH), Virus Attachment (drug effects).
MESH :
- chemical , antagonists & inhibitors : G(M1) Ganglioside, Spike Glycoprotein, Coronavirus.
- chemical , chemistry : Antiviral Agents, Azithromycin, G(M1) Ganglioside, Hydroxychloroquine, Peptidyl-Dipeptidase A, Spike Glycoprotein, Coronavirus.
- chemical , genetics : Peptidyl-Dipeptidase A, Spike Glycoprotein, Coronavirus.
- chemical , metabolism : G(M1) Ganglioside, Peptidyl-Dipeptidase A, Spike Glycoprotein, Coronavirus.
- chemical , pharmacology : Antiviral Agents, Azithromycin, Hydroxychloroquine.
- drug effects : Betacoronavirus, Host-Pathogen Interactions, Virus Attachment.
- drug therapy : Coronavirus Infections, Pneumonia, Viral.
- genetics : Host-Pathogen Interactions.
- growth & development : Betacoronavirus.
- immunology : Host-Pathogen Interactions.
- metabolism : Betacoronavirus.
- virology : Coronavirus Infections, Pneumonia, Viral.
- Amino Acid Sequence, Binding Sites, Drug Synergism, Gene Expression, Humans, Kinetics, Molecular Docking Simulation, Molecular Dynamics Simulation, Pandemics, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Sequence Alignment, Sequence Homology, Amino Acid, Thermodynamics.

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.

DOI: 10.1016/j.ijantimicag.2020.106020
PubMed: 32405156
PubMed Central: PMC7219429

Affiliations:

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Le document en format XML

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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence (MeSH)</term>
<term>Antiviral Agents (chemistry)</term>
<term>Antiviral Agents (pharmacology)</term>
<term>Azithromycin (chemistry)</term>
<term>Azithromycin (pharmacology)</term>
<term>Betacoronavirus (drug effects)</term>
<term>Betacoronavirus (growth & development)</term>
<term>Betacoronavirus (metabolism)</term>
<term>Binding Sites (MeSH)</term>
<term>Coronavirus Infections (drug therapy)</term>
<term>Coronavirus Infections (virology)</term>
<term>Drug Synergism (MeSH)</term>
<term>G(M1) Ganglioside (antagonists & inhibitors)</term>
<term>G(M1) Ganglioside (chemistry)</term>
<term>G(M1) Ganglioside (metabolism)</term>
<term>Gene Expression (MeSH)</term>
<term>Host-Pathogen Interactions (drug effects)</term>
<term>Host-Pathogen Interactions (genetics)</term>
<term>Host-Pathogen Interactions (immunology)</term>
<term>Humans (MeSH)</term>
<term>Hydroxychloroquine (chemistry)</term>
<term>Hydroxychloroquine (pharmacology)</term>
<term>Kinetics (MeSH)</term>
<term>Molecular Docking Simulation (MeSH)</term>
<term>Molecular Dynamics Simulation (MeSH)</term>
<term>Pandemics (MeSH)</term>
<term>Peptidyl-Dipeptidase A (chemistry)</term>
<term>Peptidyl-Dipeptidase A (genetics)</term>
<term>Peptidyl-Dipeptidase A (metabolism)</term>
<term>Pneumonia, Viral (drug therapy)</term>
<term>Pneumonia, Viral (virology)</term>
<term>Protein Binding (MeSH)</term>
<term>Protein Conformation, alpha-Helical (MeSH)</term>
<term>Protein Conformation, beta-Strand (MeSH)</term>
<term>Protein Interaction Domains and Motifs (MeSH)</term>
<term>Sequence Alignment (MeSH)</term>
<term>Sequence Homology, Amino Acid (MeSH)</term>
<term>Spike Glycoprotein, Coronavirus (antagonists & inhibitors)</term>
<term>Spike Glycoprotein, Coronavirus (chemistry)</term>
<term>Spike Glycoprotein, Coronavirus (genetics)</term>
<term>Spike Glycoprotein, Coronavirus (metabolism)</term>
<term>Thermodynamics (MeSH)</term>
<term>Virus Attachment (drug effects)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Alignement de séquences (MeSH)</term>
<term>Antiviraux (composition chimique)</term>
<term>Antiviraux (pharmacologie)</term>
<term>Attachement viral (effets des médicaments et des substances chimiques)</term>
<term>Azithromycine (composition chimique)</term>
<term>Azithromycine (pharmacologie)</term>
<term>Betacoronavirus (croissance et développement)</term>
<term>Betacoronavirus (effets des médicaments et des substances chimiques)</term>
<term>Betacoronavirus (métabolisme)</term>
<term>Cinétique (MeSH)</term>
<term>Expression des gènes (MeSH)</term>
<term>Ganglioside GM1 (antagonistes et inhibiteurs)</term>
<term>Ganglioside GM1 (composition chimique)</term>
<term>Ganglioside GM1 (métabolisme)</term>
<term>Glycoprotéine de spicule des coronavirus (antagonistes et inhibiteurs)</term>
<term>Glycoprotéine de spicule des coronavirus (composition chimique)</term>
<term>Glycoprotéine de spicule des coronavirus (génétique)</term>
<term>Glycoprotéine de spicule des coronavirus (métabolisme)</term>
<term>Humains (MeSH)</term>
<term>Hydroxychloroquine (composition chimique)</term>
<term>Hydroxychloroquine (pharmacologie)</term>
<term>Infections à coronavirus (traitement médicamenteux)</term>
<term>Infections à coronavirus (virologie)</term>
<term>Interactions hôte-pathogène (effets des médicaments et des substances chimiques)</term>
<term>Interactions hôte-pathogène (génétique)</term>
<term>Interactions hôte-pathogène (immunologie)</term>
<term>Liaison aux protéines (MeSH)</term>
<term>Motifs et domaines d'intéraction protéique (MeSH)</term>
<term>Pandémies (MeSH)</term>
<term>Peptidyl-Dipeptidase A (composition chimique)</term>
<term>Peptidyl-Dipeptidase A (génétique)</term>
<term>Peptidyl-Dipeptidase A (métabolisme)</term>
<term>Pneumopathie virale (traitement médicamenteux)</term>
<term>Pneumopathie virale (virologie)</term>
<term>Similitude de séquences d'acides aminés (MeSH)</term>
<term>Simulation de docking moléculaire (MeSH)</term>
<term>Simulation de dynamique moléculaire (MeSH)</term>
<term>Sites de fixation (MeSH)</term>
<term>Structure en brin bêta (MeSH)</term>
<term>Structure en hélice alpha (MeSH)</term>
<term>Synergie des médicaments (MeSH)</term>
<term>Séquence d'acides aminés (MeSH)</term>
<term>Thermodynamique (MeSH)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>G(M1) Ganglioside</term>
<term>Spike Glycoprotein, Coronavirus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term>
<term>Azithromycin</term>
<term>G(M1) Ganglioside</term>
<term>Hydroxychloroquine</term>
<term>Peptidyl-Dipeptidase A</term>
<term>Spike Glycoprotein, Coronavirus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Peptidyl-Dipeptidase A</term>
<term>Spike Glycoprotein, Coronavirus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>G(M1) Ganglioside</term>
<term>Peptidyl-Dipeptidase A</term>
<term>Spike Glycoprotein, Coronavirus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term>
<term>Azithromycin</term>
<term>Hydroxychloroquine</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Ganglioside GM1</term>
<term>Glycoprotéine de spicule des coronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Antiviraux</term>
<term>Azithromycine</term>
<term>Ganglioside GM1</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Hydroxychloroquine</term>
<term>Peptidyl-Dipeptidase A</term>
</keywords>
<keywords scheme="MESH" qualifier="croissance et développement" xml:lang="fr"><term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Betacoronavirus</term>
<term>Host-Pathogen Interactions</term>
<term>Virus Attachment</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Attachement viral</term>
<term>Betacoronavirus</term>
<term>Interactions hôte-pathogène</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Host-Pathogen Interactions</term>
</keywords>
<keywords scheme="MESH" qualifier="growth & development" xml:lang="en"><term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Glycoprotéine de spicule des coronavirus</term>
<term>Interactions hôte-pathogène</term>
<term>Peptidyl-Dipeptidase A</term>
</keywords>
<keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Interactions hôte-pathogène</term>
</keywords>
<keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Host-Pathogen Interactions</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Betacoronavirus</term>
<term>Ganglioside GM1</term>
<term>Glycoprotéine de spicule des coronavirus</term>
<term>Peptidyl-Dipeptidase A</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term>
<term>Azithromycine</term>
<term>Hydroxychloroquine</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
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<term>Binding Sites</term>
<term>Drug Synergism</term>
<term>Gene Expression</term>
<term>Humans</term>
<term>Kinetics</term>
<term>Molecular Docking Simulation</term>
<term>Molecular Dynamics Simulation</term>
<term>Pandemics</term>
<term>Protein Binding</term>
<term>Protein Conformation, alpha-Helical</term>
<term>Protein Conformation, beta-Strand</term>
<term>Protein Interaction Domains and Motifs</term>
<term>Sequence Alignment</term>
<term>Sequence Homology, Amino Acid</term>
<term>Thermodynamics</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Alignement de séquences</term>
<term>Cinétique</term>
<term>Expression des gènes</term>
<term>Humains</term>
<term>Liaison aux protéines</term>
<term>Motifs et domaines d'intéraction protéique</term>
<term>Pandémies</term>
<term>Similitude de séquences d'acides aminés</term>
<term>Simulation de docking moléculaire</term>
<term>Simulation de dynamique moléculaire</term>
<term>Sites de fixation</term>
<term>Structure en brin bêta</term>
<term>Structure en hélice alpha</term>
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<term>Séquence d'acides aminés</term>
<term>Thermodynamique</term>
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<front><div type="abstract" xml:lang="en">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.</div>
</front>
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<DateCompleted><Year>2020</Year>
<Month>09</Month>
<Day>01</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>09</Month>
<Day>02</Day>
</DateRevised>
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<JournalIssue CitedMedium="Internet"><Volume>56</Volume>
<Issue>2</Issue>
<PubDate><Year>2020</Year>
<Month>Aug</Month>
</PubDate>
</JournalIssue>
<Title>International journal of antimicrobial agents</Title>
<ISOAbbreviation>Int. J. Antimicrob. Agents</ISOAbbreviation>
</Journal>
<ArticleTitle>Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal.</ArticleTitle>
<Pagination><MedlinePgn>106020</MedlinePgn>
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<ELocationID EIdType="doi" ValidYN="Y">10.1016/j.ijantimicag.2020.106020</ELocationID>
<Abstract><AbstractText>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.</AbstractText>
<CopyrightInformation>© 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Fantini</LastName>
<ForeName>Jacques</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>INSERM UMR_S 1072, 13015 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chahinian</LastName>
<ForeName>Henri</ForeName>
<Initials>H</Initials>
<AffiliationInfo><Affiliation>Aix-Marseille Université, 13015 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Yahi</LastName>
<ForeName>Nouara</ForeName>
<Initials>N</Initials>
<AffiliationInfo><Affiliation>Aix-Marseille Université, 13015 Marseille, France.</Affiliation>
</AffiliationInfo>
</Author>
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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.

Synergistic 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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