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

Area of Science:

• Organic Chemistry
• Immunology
• Virology

Background:

• Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and liver/lymph node-specific intercellular adhesion molecule-3-grabbing integrin (L-SIGN) mediate human immunodeficiency virus 1 (HIV-1) attachment to immune cells.
• Blocking this attachment is a key strategy for developing early-stage antiretroviral agents.
• Lewis-based inhibitors for this target are underexplored compared to mannose- and fucose-based ligands.

Purpose of the Study:

• To synthesize novel Lewis-X-containing triterpenoid saponins.
• To evaluate their potential as inhibitors of DC-SIGN- and L-SIGN-mediated HIV-1 transfer.

Main Methods:

• Convergent synthesis of Lewis-X triterpenoid saponins featuring betulinic acid and echinocystic acid aglycones.
• Utilized thioglycoside and trichloroacetimidate glycosylation chemistries in a six-step linear synthesis.
• Assessed inhibitory activity against HIV-1 transfer to CD4-positive cells mediated by DC-SIGN and L-SIGN.

Main Results:

• Successfully synthesized Lewis-X triterpenoid saponins with betulinic acid and echinocystic acid.
• Demonstrated potent inhibition of DC-SIGN- and L-SIGN-mediated HIV-1 transfer.
• Achieved IC50 values in the low micromolar range (21-50 µM), indicating strong antiviral activity.

Conclusions:

• Lewis-X-containing triterpenoid saponins are potent monovalent inhibitors of HIV-1 transfer.
• This study provides a foundation for developing saponin-based antiviral agents targeting immune cells.
• Highlights the potential of Lewis-based inhibitors in HIV-1 prevention strategies.