DC-SIGN and L-SIGN are two C-type lectin receptors (CLRs) used by SARS-CoV-2 as viral co-receptors. SARS-CoV-2 manipulates both DC-SIGN and L-SIGN to enhance infection, raising interest in developing antagonists for these receptors. These two receptors, very similar (82% identity), have different localizations. DC-SIGN, found in dendritic cells, shapes the immune response by recognizing carbohydrate patterns on pathogens. In contrast, L-SIGN is expressed in endothelial cells of the respiratory tract. The main threat posed by COVID-19 is the hyperactivation of the immune system, which is exacerbated if DC-SIGN is engaged with exogenous ligands. Therefore, L-SIGN, which is co-localized with ACE2-expressing cells in the respiratory tract, is a more suitable target for anti-adhesion therapy. Designing a selective ligand for L-SIGN is a challenge due to the high sequence identity between the two lectins.
The MIT team from the M&P group at IBS, in collaboration with teams from the Universities of Milan and Madrid, developed here an antagonist, Man84. This glycomimetic, a mannose derivative, binds to L-SIGN with a Kd of 12.7 μM and is the first known selective ligand for it, showing 50 times more selectivity compared to DC-SIGN. The X-ray structure of the L-SIGN/Man84 complex reveals the role of the guanidinium group at position 2 in achieving steric and electrostatic complementarity with the binding site. The source of the selectivity lies in a single amino acid difference between the two receptors within their recognition site. Dimeric versions of Man84 allow for additional avidity in the nanomolar range. These compounds inhibit L-SIGN-dependent trans-infection for both SARS-CoV-2 and Ebola virus and exhibit the highest avidity reported to date for low-valence glycomimetics targeting CLRs.
They represent promising tools to combat viral anchoring in the respiratory tract and hold potential for other medical applications. This work is subject to a patent between UGA and the University of Milan.
Unprecedented selectivity for homologous lectin targets : differential targeting of the viral receptors L-SIGN and DC-SIGN. Delaunay C, Pollastri S, Thépaut M, et al. Chem Sci. 2024 ; DOI : 10.1039/d4sc02980a.
Contact : Franck Fieschi, Membrane and Pathogens Group (IBS/M&P)