Multivalent DC-SIGN ligands with a rigid core of controlled lenght

Human immunodeficiency virus (HIV) is still a huge health problem of the 21st century, 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, dendritic cell-specific ICAM-3 grabbing non-integrine (DC-SIGN), expressed at the surface of the mucosal dendritic cells (DC) and involved in the early stages of HIV infection, is an important cellular target.1 DC-SIGN is a calcium-dependant tetrameric lectin; it recognizes high-mannose oligosaccharides displayed at the surface of HIV virus and interacts with them through strong multiple interactions. Therefore, artificial molecules displaying multivalent carbohydrate moieties, able to interact with DC-SIGN with good affinity, should prevent HIV attachment to DC and therefore HIV infection. In our group, several DC-SIGN mannose-based ligands have been prepared and tested as HIV inhibitors; glycomimetic compounds were used rather than native oligosaccharides.2, 3 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. 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 tests results will be presented.