Increasing the Chemical Space of L-SIGN Specific Glycomimetics

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 <b>Man84</b>, binds to L-SIGN with micromolar affinity and high-selectivity against the homologue lectin DC-SIGN. Here we describe a series of <b>Man84</b> isosteres (ligands <b>2-11</b>) 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 <b>4</b>, <b>5</b> and <b>9</b> were found to bind to L-SIGN with low micromolar affinity and 50-94-fold selectivity, thus matching or exceeding the performance of <b>Man84</b>. The crystal structure of the L-SIGN CRD/<b>4</b> 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.