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Using a combination of structural and molecular modeling approaches, we showed that chloroquine (CLQ), one of the drugs currently under investigation for SARS-CoV-2 treatment, binds sialic acids and gangliosides with high affinity. We identified a new type of ganglioside-binding domain at the tip of the N-terminal domain of the SARS-CoV-2 spike (S) protein. This domain (aa 111-158), which is fully conserved among clinical isolates worldwide, may improve the attachment of the virus to lipid rafts and facilitate the contact with the ACE-2 receptor. We showed that in presence of CLQ (or of the more active derivative hydroxychloroquine, CLQ-OH), the viral spike 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 SARS-CoV-2 infected patients and stop the pandemic. 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