Multivalent DC-SIGN Ligands With a Rigid Core of Controlled Length

Human immunodeficiency virus (HIV) is still a huge health problem, causing the death of over 1 million people per year. The search for HIV-entry inhibitors represents a promising challenge to prevent HIV infection. In this field, DC-SIGN, a receptor expressed at the surface of the mucosal dendritic cells and involved in the early stages of HIV infection, is an important cellular target.1 DC-SIGN is a calcium-dependant tetrameric lectin, which recognizes and binds high-mannose oligosaccharides displayed at the surface of HIV virus. The use of artificial molecules displaying multivalent carbohydrate moieties, able to interact with DC-SIGN with good affinity, should represent a therapeutic strategy in order to prevent HIV attachment to dendritic cells. Here we present a library of multivalent glycomimetic compounds potentially able to bind simultaneously two binding sites on DC-SIGN, thus exploiting the chelating binding mode to enhance their affinity for the target. Compounds were synthesised by varying the length of a rigid aromatic scaffold and the nature as well as the valency of the sugar moieties at each end of the central core. Every synthesised compound has been tested as HIV inhibitor through Surface Plasmon Resonance (SPR) inhibition assays. Some of the synthesised compounds were tested for the ability to inhibit HIV transmission in an in vitro trans infection assay, revealing a high activity that seems depend on scaffold length. Tests were performed by Dr. Angela Berzi, in the laboratories of Prof. Mario Clerici (University of Milan). Synthetic pathways and biological tests will be presented, together with preliminary evaluation of compounds morphological behaviour in aqueous solution.