Man-based glycomimetics inhibit DC/L-SIGN interaction with SARS-CoV-2 spike protein

DC-SIGN and its homologue L-SIGN are two tetrameric transmembrane C-type lectins that share 77% of their amino-acidic sequence. Despite their high similarity, some important differences are present: DC-SIGN is expressed by immature dendritic cells located on dermal and mucosal tissues and can recognize both mannosylated and fucosylated structures; while L-SIGN expression is limited to specific tissues (e.g. lungs, liver and lymph-nodes) and preferentially binds mannose-containing carbohydrates. They are well known receptor for glycosylated pathogens (e.g. HIV-1, Ebola, Dengue) and were recently identified as entry co-factors for SARS-CoV-2. Since L-SIGN is co-expressed with ACE2 on respiratory tract cells, the need for potent and selective antagonist is real and urgent. Over the past decades, several efforts have been made for the development of DC-SIGN ligands as inhibitors of DC-SIGN mediated infections; however, no ligands have been reported so far to bind to L-SIGN. Here, we present the first set of mannose-based glycomimetic ligands which bind to L-SIGN in an SPR inhibition experiment showing that they inhibit binding of both DC-SIGN and L-SIGN to immobilized SARS-CoV-2 spike protein. All the ligands examined present a mannose residue modified at position 2 with a triazole moiety, both as a part of a pseudo-dimannoside or as a monosaccharide. The design, synthesis and activity evaluation of the ligands will be discussed.