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

Abstract 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 IC 50  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.