De novo macrocyclic glycopeptides by mRNA display to target macrophage galactose type lectin on dendritic cells

Carbohydrates serve as key recognition elements in cellular communication. Lectins are important protein elements in this communication, recognizing specific extracellular glycosylation patterns and translating this into an intracellular signal. For example, the macrophage galactose-type lectin (MGL) on dendritic cells recognizes terminal GalNAc sugars and stimulates anti-inflammatory pathways. These proteins thus represent a potential means to steer immune activation, if suitably precise and potent ligands can be found. In this work we attempt to address this challenge using mRNA display of peptides generated under a reprogrammed genetic code and chemically post-translationally modified with a monosaccharide. A library of macrocyclic glycopeptides was built and its screening for binding to MGL optimized, resulting in a hit that is able to bind MGL at sub-micromolar concentrations and stimulate IL-10 production by monocyte-derived dendritic cells.