C-5 modification of β-Fucosides as a strategy for targeting the BC2L-C Lectin

Burkholderia cenocepacia is a multidrug-resistant Gram-negative pathogen associated with severe opportunistic infections, particularly in cystic fibrosis and immunocompromised patients. A critical step in its pathogenesis is bacterial adhesion to host tissues, primarily mediated by lectin–carbohydrate interactions, notably through the superlectin BC2L-C. Targeting BC2L-C represents a promising strategy to disrupt early stages of infection. In this context, we focused on the modification of β-fucoside scaffolds at the C-5 position, aiming to reaching secondary interaction sites within the lectin and to enable multivalent ligand design. To achieve this, we employed a decatungstate anion (TBADT)-mediated photochemical Giese-type alkylation that was recently developed in our group for the late-stage functionalization of β-fucosides. Conformational analysis and molecular docking studies were performed to evaluate the spatial orientation, flexibility, and binding potential of the C-5-functionalized fucoside scaffolds within the fucose-binding pocket of BC2L-C, thereby guiding the rational design of next-generation glycomimetics. The synthesized compounds are being fully characterized and will be evaluated for their binding affinity to BC2L-C using NMR-based biophysical techniques, enabling the detection and analysis of ligand–lectin interactions at the molecular level. This research was supported by NextGeneration EU-MURPNRR Extended Partnership initiative on Emerging Infectious Diseases (Project no. PE00000007, INF-ACT).