1  Introduction
The recent emergence of the novel pathogenic SARS-coronavirus 2 (SARS-CoV-2) is responsible for a global pandemic [1], and there is an urgent need to identify active antiviral agents. Given the global health emergency, drug repositioning is the most reliable option to design an efficient therapy for infected patients without delay [2,3]. Several drugs have already been tested, among which chloroquine (CLQ), a well-known antimalarial drug, is one of the most promising as it has shown apparent efficacy in the treatment of COVID-19-associated pneumonia in recent clinical studies [4]. However, the mechanism of action of CLQ against SARS-CoV-2 is unclear as the drug seems to exert a broad range of potential antiviral effects [5]. Therefore, although CLQ is classically considered as an inhibitor of endocytic pathways through elevation of endosomal pH [6], its detailed molecular mechanism of action as an antiviral compound remains unclear [3,5]. Interestingly, CLQ has been shown to interfere with the terminal glycosylation of angiotensin-converting enzyme-2 (ACE-2) [7], which acts as a plasma membrane receptor for both SARS-CoV [8] and SARS-CoV-2 [9], and CLQ could act at several steps of the coronavirus replication cycle [7]. These data suggest the interesting and mostly unexplored possibility that CLQ could prevent viral attachment through a direct effect on host cell surface molecules.
One important characteristic of human coronaviruses is that besides their protein membrane receptor, they also depend upon sialic-acid-containing glycoproteins and gangliosides that act as primary attachment factors along the respiratory tract [10]. The present study used a combination of structural and molecular modelling approaches [11] to investigate the potential interaction between CLQ and sialic acids. A ganglioside-binding site in the N-terminal domain (NTD) of the spike (S) glycoprotein of SARS-CoV-2 was identified, and CLQ was shown to be a potential blocker of the S–ganglioside interaction which occurs in the first step of the viral replication cycle (i.e. attachment to the surface of respiratory cells, mediated by the S protein). In addition, the antiviral potential of CLQ and its derivative hydroxychloroquine (CLQ-OH) against SARS-CoV-2 were compared. Overall, this study found that CLQ and CLQ-OH may be used to fight pathogenic human coronaviruses [3], [4], [5], [6], including SARS-CoV-2 [12].