Mono- and Multivalent Glycomimetics Targeting Dendritic Cells as Novel Tools for Infectious Diseases and Cancer

The recognition of complex carbohydrate epitopes on the surface of pathogens or aberrant cells is a hallmark of the innate immune system. Dendritic cells (DCs) are equipped with a variety of lectin receptors that bind and internalize glycosylated cells in a context dependent manner.[1] This event is often coupled with the induction of specific immune responses tailored to the stimulus encountered by the DC. Carbohydrate-based drugs that mimic the structure of certain glycan epitopes represent an underappreciated tool for the modulation of innate immune functions in a disease-related context. In this context, the C-type lectin receptor dendritic cell-specific intermolecular adhesion molecule 3 grabbing non-integrin (DC-SIGN) represents a particularly attractive target. DC-SIGN acts as a pathological host factor in viral infections, enabling either direct infection of DCs, or virus dissemination through the lymphatic system.[2] In addition, DC-SIGN is highly expressed on competent antigen-presenting immature DCs, as well as on tumor associated DCs and macrophages, thus making it a prime target for immune modulation, drug/vaccine delivery, and theranostic tumor targeting. Here, the development of DC-SIGN-targeted glycomimetics and carbohydrate-based multivalent compounds is presented. An optimization campaign starting from mannose as the minimal DC-SIGN ligand resulted in the discovery of a potent glycomimetic compound.[3,4] Key insights about the formation of a cooperative interaction network in the DC-SIGN binding site were obtained by X-ray crystallography combined with a thorough analysis of the interaction thermodynamics. The combination of a stereospecific hydrogen bond and an electrostatic polarization of the network was identified as the origin for the non-additive enthalpy enhancement. A complementary strategy to target cell surface lectins relies on the multivalent presentation of carbohydrate epitopes on oligo- or multivalent scaffolds.[3,5-6] A series of multivalent compounds bearing cognate glycan epitopes efficiently target DC-SIGN-expressing cells and inhibit virus binding in a cellular SARS-CoV-2 infection model. These ligands leverage multivalent affinity enhancement effects to reach up to picomolar affinities. It is further demonstrated that multivalent molecules can benefit from the introduction of potent and selective glycomimetic epitopes to leverage enthalpy-driven multivalent enhancement. These insights pave the way for a further development of DC-SIGN-targeting mono- and multivalent compounds as multi-purpose tools in the context of infectious diseases and cancer.