Melanin Building Block as Scaffold for Dynamic Submicromolar Galectin Inhibitors

Galectins, β-galactoside-binding soluble proteins, are involved in a multitude of biological functions and several diseases, so numerous galectin inhibitors, from small molecules to multivalent glycoconjugates, have been developed and investigated as tools for therapeutic applications. Notably, multivalent ligands on a biocompatible backbone offer a promising perspective for creating high-performance selective inhibitors with nanomolar affinity. Leveraging the oxidative polymerization of 5,6-dihydroxyindole (DHI), a key intermediate of eumelanin pigments, here, we present the synthesis and complete nuclear magnetic resonance characterization of a submicromolar multivalent ligand of galectin-3 based on a naturally biocompatible eumelanin backbone. The integration of several complementary techniques, namely, UV–vis spectrometry, dynamic light scattering, isothermal titration calorimetry, and biolayer interferometry, in the investigation of galectin-3–eumelanin-related ligand interactions, allowed us to calculate the KD and to propose a model for the protein–polymer interaction.