Fucosylated ubiquitin and orthogonally glycosylated mutant A28C: conceptually new ligands for Burkholderia ambifaria lectin (BambL)

06 November 2020
Our new article published in Chemical Science report on developing conceptually new inhibitors towards receptors of lung pathogens with high resistance to antibiotics. The BambL lectin from Burkholderia bind to fucose present on lung tissue. In collaboration with colleagues in Firenze, we developed high affinity ligands for BambL able to attach to adjacent sites on the lectin with high affinity and high specificity. A small protein scaffold has been functionalized with several fucose analogs, resulting in strong avidity towards BambL. In addition, rhamnose, a sugar able to modulate the activities of our white cells, was also grafted on the scaffold in order to boosta a better response to infection./ Figure: Crystal structure of BambL lectin in complex with new fucose based glycomimetics (X-ray structure by Dr. Sakonwan Kuhaudomlarp)

“Two orthogonal, metal free click reactions, enabled to glycosylate ubiquitin and its mutant A28C forming two protein scaffolds with high affinity for BambL, a lectin from the human pathogen Burkholderia ambifaria. A new fucoside analogue, with high affinity with BambL, firstly synthetized and co-crystallized with the protein target, provided the insights for sugar determinants grafting onto ubiquitin. Three ubiquitin-based glycosides were thus assembled. Fuc-Ub, presented several copies of the fucoside analogue, with proper geometry for multivalent effect; Rha-A28C, displayed one thio-rhamnose, known for its ability to tuning the immunological response; finally, Fuc-Rha-A28C, included both multiple fucoside analogs and the rhamnose residue. Fuc-Ub and Fuc-Rha-A28C ligands proved high affinity for BambL and unprecedented immune modulatory properties towards macrophages activation.”

The article is availaible over here: https://pubs.rsc.org/en/content/articlelanding/2020/sc/d0sc03741a#!divAbstract