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 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.