Synthetic Ligands of Myeloid C-Type Lectin Receptors

C-type lectin receptors (CLRs) are one of the major classes of pattern recognition receptors. They mediate numerous biological events, including cell adhesion, pathogen recognition, and innate immune responses. Initial recognition of a pathogen by specific CLRs shapes the inflammatory landscape of the host, and the resulting immune response can be protective but can also contribute to immune-mediated pathology. Understanding the binding of CLRs to their ligands has gained increasing attention and triggered research in the fields of structural biology, pathogen recognition, and immune signaling. Of critical importance for understanding the factors that affect binding and, therefore, being able to therapeutically exploit CLRs as druggable targets, is the identification of binding epitopes and drug-like analogs. Hence, informed tailoring of candidate molecules can enhance affinities, exploit avidity, and enable the design of novel ligands. This review surveys the extensive diversity that has been generated in the area of synthetic myeloid CLR ligands, focusing on the dendritic cell-specific ICAM3-grabbing non-integrin receptor (DC-SIGN), macrophage-inducible C-type lectin (Mincle), dendritic cell-associated C-type lectin-1 (Dectin-1), and langerin. Context is rendered via the description of binding modes, signaling pathways, and therapeutic opportunities, which facilitates the identification of current limitations and potential future directions of the field.