G. Cavazzoli, C. Delaunay, S. Pollastri, A. Panzeri, S. Sattin, M.Thépaut, L. Belvisi, F. Fieschi, A. Bernardi
J. Med. Chem. (2025)
Selective ligands for the C-type lectin receptor L-SIGN offer promising avenues in antiviral therapies and for tissue-specific delivery. We recently reported that a guanidine-bearing modified mannose glycomimetic, called Man84, binds to L-SIGN with micromolar affinity and high-selectivity against the homologue lectin DC-SIGN. Here we describe a series of Man84 isosteres (ligands 2–11) that maintain or improve on this selectivity. The affinity of the ligands for L-SIGN, as well as their selectivity against DC-SIGN, were evaluated by Surface Plasmon Resonance inhibition assays using immobilized SARS-CoV-2 Spike protein. Compounds 4, 5 and 9 were found to bind to L-SIGN with low micromolar affinity and 50–94-fold selectivity, thus matching or exceeding the performance of Man84. The crystal structure of the L-SIGN CRD/4 complex was solved and highlighted the critical role of a bidentate H-bond interaction of the ligands with the side chain of E370 in L-SIGN.