The chemical structure of ATM is shown in Fig. 1 a. The molecule contains two sugar-like pyranyl rings, one with a nitrogen-containing group (N-pyr), the other with an acetyl group (Ac-pyr). The remaining part of the molecule is cyclic, so that its overall conformational flexibility, although significant, is restricted to a limited spatial volume of 2082 Å3 (Fig. 1b). Interestingly, this volume is almost the same as that of the saccharide part of ganglioside GM1 (2293 Å3, Fig. 1b), a lipid raft ganglioside that plays a critical role in the binding and endocytosis of respiratory viruses [26], including pathogenic human coronaviruses [27]. Beyond their similar spatial volume, the saccharide part of GM1 and ATM also share some analogous chemical features, including sugar rings and a solvent-accessible surface dotted with several CH and OH groups (Fig. 1b). This molecular similarity is further illustrated in Figure S1 where ATM is superimposed on the saccharide part of GM1.
Fig. 1 Structures of azithromycin (ATM) and SARS-CoV-2 spike protein trimer. (a) ATM, with both sugar-like pyranyl groups N-pyr and Ac-pyr indicated. The molecules are shown in chemical, tube and sphere rendering (carbon in green, nitrogen in blue, oxygen in red, hydrogen in white). (b) Molecular structure similarity between ATM and the saccharide part of ganglioside GM1. Both structures can adopt a globular shape the surface of which is covered with a patchwork of OH (arrows 1 and 2) and CH groups (arrow 3). The volume occupied by ATM and the saccharide part of GM1 can be estimated to be 2082 and 2293 Å3, respectively. (c) front and above views of the trimeric spike, each spike protein subunit with a distinct surface colour (cyan for chain A, yellow for chain B, purple for chain C). Atoms belonging to the ganglioside-binding domain of each subunit are visible underneath the slightly transparent surface. The ganglioside-binding domains, the NTD and the RBD are indicated.