Lewis-X-Containing Triterpenoid Saponins Inhibit DC-SIGN- and L-SIGN-Mediated Transfer of HIV-1 Infection

Blocking dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)- and liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN)-mediated human immunodeficiency virus 1 (HIV-1) attachment to immune cells represents a promising strategy for developing antiretroviral agents effective during the early stages of sexual transmission. Although mannose- and fucose-based ligands have received considerable attention, Lewis-based inhibitors remain relatively underexplored. In this study, we report the first synthesis of Lewis-X-containing triterpenoid saponins featuring betulinic acid and echinocystic acid as aglycones. These saponins were stereoselectively and efficiently synthesized in six linear steps using a convergent approach that leveraged thioglycoside and trichloroacetimidate glycosylation chemistries. Notably, our findings demonstrate that these Lewis-X-containing triterpenoid saponins are among the most potent monovalent inhibitors reported to date of DC-SIGN- and L-SIGN-mediated transfer of HIV-1 infection to CD4-positive cells, with IC₅₀ values in the low micromolar range (21-50 µM). This work lays a valuable foundation for the development of saponin-based antiviral agents targeting immune cells.