Glycomimetic ligands acting as selective antagonists of L-SIGN

DC-SIGN and L-SIGN – also referred to as Dendritic Cell-Specific Intracellular Adhesion molecules (ICAM)-3 Grabbing Non-integrin (CD209) and Liver/Lymphnode-Specific ICAM-3 Grabbing Non-integrin (CD209L), respectively – are two C-type lectin receptors (CLRs), sharing 77% of their amino acidic sequences.1 They are able to bind to glycan motifs directly expressed at the surface of different pathogens thanks to a Ca2+ ion in the binding site – the so-called Carbohydrate Receptor Domain (CRD) – suddenly inducing the activation of the initial stages of adaptive immune response. Nevertheless, several deadly viruses – such as HIV, Ebola, hepatitis C viruses, Dengue and West Nile virus – have developed strategies to subvert the function of CLRs to escape antiviral immunity and promote infection.2 Beyond the cited microorganisms, DC-SIGN and L-SIGN have been recently found to be entry co-factors for SARS-CoV-2, promoting trans-infection of ACE2-expressing cells.3,4 Interestingly, while fundamental studies have been performed in last years to design and characterize molecules acting as inhibitors of DC-SIGN-mediated infections, the first set of mannose-based ligands for L-SIGN was reported by our group only in 2022.5 According to this paper, the tested glycomimetics could inhibit the interaction of both lectins with the SARS-CoV-2 spike glycoprotein in a Surface Plasmon Resonance (SPR) assay and are more potent than mannose by up to 36-fold (DC-SIGN) and 10-fold (L-SIGN). In this context, we present a new set of mannose-based glycomimetics which could selectively inhibit L-SIGN against DC-SIGN. All the molecules are based on a mono-mannose scaffold, modified at position 2 with a triazole moiety.