C2-Triazole-modified mannose-based L-SIGN antagonists

L-SIGN - Liver/lymph node-specific ICAM-3-grabbing integrin – is a tetrameric transmembrane C-type lectin, which shares 77% amino acid sequence with DC-SIGN and displays similar activity for highly mannosylated oligosaccharides. It is expressed in human lungs in type II alveolar cells and in endothelial cells and has recently been characterized as an entry co-factor for SARS-CoV-2. Over the past decades, important 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.