Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection
Fantini et al.
, Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and..
, Int J Antimicrob Agents, 55:5, doi:10.1016/j.ijantimicag.2020.105960 (Theory)
In Silico analysis confirming the antiviral properties of CQ, showing a new mechanism of action of CQ, and showing that HCQ is more potent than CQ.
Fantini et al., 3 Apr 2020, peer-reviewed, 4 authors.
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International Journal of Antimicrobial Agents 55 (2020) 105960
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents
journal homepage: www.elsevier.com/locate/ijantimicag
Structural and molecular modelling studies reveal a new mechanism
of action of chloroquine and hydroxychloroquine against SARS-CoV-2
Jacques Fantini a,b,∗, Coralie Di Scala c, Henri Chahinian a,b, Nouara Yahi a,b
INSERM UMR_S 1072, Marseille, France
Department of Biology, Aix-Marseille Université, Marseille, France
INMED, INSERM U1249, Parc Scientiﬁque de Luminy, Marseille, France
a r t i c l e
i n f o
Editor: Jean-Marc Rolain
a b s t r a c t
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 SARSCoV-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.
© 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
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