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Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection.
Int J Antimicrob Agents. 2020 May; 55(5):105960.IJ

Abstract

The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation.

Authors+Show Affiliations

INSERM UMR_S 1072, Marseille, France; Department of Biology, Aix-Marseille Université, Marseille, France. Electronic address: jacques.fantini@univ-amu.fr.INMED, INSERM U1249, Parc Scientifique de Luminy, Marseille, France.INSERM UMR_S 1072, Marseille, France; Department of Biology, Aix-Marseille Université, Marseille, France.INSERM UMR_S 1072, Marseille, France; Department of Biology, Aix-Marseille Université, Marseille, France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32251731

Citation

Fantini, Jacques, et al. "Structural and Molecular Modelling Studies Reveal a New Mechanism of Action of Chloroquine and Hydroxychloroquine Against SARS-CoV-2 Infection." International Journal of Antimicrobial Agents, vol. 55, no. 5, 2020, p. 105960.
Fantini J, Di Scala C, Chahinian H, et al. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int J Antimicrob Agents. 2020;55(5):105960.
Fantini, J., Di Scala, C., Chahinian, H., & Yahi, N. (2020). Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. International Journal of Antimicrobial Agents, 55(5), 105960. https://doi.org/10.1016/j.ijantimicag.2020.105960
Fantini J, et al. Structural and Molecular Modelling Studies Reveal a New Mechanism of Action of Chloroquine and Hydroxychloroquine Against SARS-CoV-2 Infection. Int J Antimicrob Agents. 2020;55(5):105960. PubMed PMID: 32251731.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. AU - Fantini,Jacques, AU - Di Scala,Coralie, AU - Chahinian,Henri, AU - Yahi,Nouara, Y1 - 2020/04/03/ PY - 2020/03/16/received PY - 2020/03/21/accepted PY - 2020/4/7/pubmed PY - 2020/5/29/medline PY - 2020/4/7/entrez KW - Chloroquine KW - Coronavirus KW - Ganglioside KW - Pandemic KW - SARS-CoV-2 KW - Spike SP - 105960 EP - 105960 JF - International journal of antimicrobial agents JO - Int J Antimicrob Agents VL - 55 IS - 5 N2 - The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a worldwide pandemic. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay. The first step of the viral replication cycle [i.e. attachment to the surface of respiratory cells, mediated by the spike (S) viral protein] offers several potential therapeutic targets. The S protein uses the angiotension-converting enzyme-2 (ACE-2) receptor for entry, but also sialic acids linked to host cell surface gangliosides. Using a combination of structural and molecular modelling approaches, this study showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. A new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 S protein was identified. This domain (111-158), which is fully conserved among clinical isolates worldwide, may improve attachment of the virus to lipid rafts and facilitate contact with the ACE-2 receptor. This study showed that, in the presence of CLQ [or its more active derivative, hydroxychloroquine (CLQ-OH)], the viral S protein is no longer able to bind gangliosides. The identification of this new mechanism of action of CLQ and CLQ-OH supports the use of these repositioned drugs to cure patients infected with SARS-CoV-2. The in-silico approaches used in this study might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before clinical evaluation. SN - 1872-7913 UR - https://www.unboundmedicine.com/medline/citation/32251731/Structural_and_molecular_modelling_studies_reveal_a_new_mechanism_of_action_of_chloroquine_and_hydroxychloroquine_against_SARS_CoV_2_infection_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0924-8579(20)30110-2 DB - PRIME DP - Unbound Medicine ER -