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Structural and molecular modeling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection.
The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a global pandemic. In face of the 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. the attachment to the surface of respiratory cells mediated by the spike (S) viral protein, offers several potential therapeutic targets. The S protein uses the ACE-2 receptor for entry, but also sialic acids linked to host cell surface gangliosides. 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. Our in silico approaches might also be used to assess the efficiency of a broad range of repositioned and/or innovative drug candidates before their clinical evaluation.
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