Yunzhan Ning, Amol Ugale, Natalija Simonović, Bita Rashidfarokhi, Sachchidanand Tiwari, Hiromi Muramatsu, Iris A. Bermejo, Alexander Rührnößl, Alina Markhof, Dacheng Hong, Jonathan Lefèbre, Christine Radtke, Norbert Pardi, Christoph Rademacher
C-type lectin langerin plays a pivotal role in glycan recognition during immune surveillance, making it a promising target for glycomimetic-based targeted delivery strategies. However, differences in glycan recognition and receptor expression between human and murine homologs often complicate translational studies. Here, we report a structure-guided approach to overcome this barrier for a previously developed glycomimetic ligand. While this glycomimetic binds human langerin, it fails to interact with murine receptor due to a steric clash with murine langerin. However, its α-anomer counterpart avoided the clash, binding to murine langerin while maintaining affinity for the human receptor. Notably, the α-anomer enables enhanced mRNA translation in both murine and human ex vivo . These findings underscore the significance of the anomeric configuration of glucosamine derivatives in langerin recognition and offer a rational strategy for designing glycomimetic ligands targeting langerin. Our study highlights how a stereo center can be leveraged to fine-tune glycomimetic-lectin specificity.