Druggable allosteric sites in β‐propeller lectins

Elena Shanina (1) , Sakonwan Kuhaudomlarp (2) , Kanhaya Lal (2) , Peter Seeberger (1) , Anne Imberty (2) , Christoph Rademacher (1)

1 Max Planck Institute of Colloids and Interfaces
2 CERMAV - Centre de Recherches sur les Macromolécules Végétales

Carbohydrate-binding proteins (lectins) are auspicious targets to combat antimicrobial resistance; however, its noncarbohydrate drug-like inhibitors are still spacious. Here, we present a druggable pocket in a β-propeller lectin BambL from Burkholderia ambifaria as a potential target for allosteric inhibitors. This site was identified employing 19F NMR fragment screening and a computational pocket prediction algorithm SiteMap. The structure-activity relationship study revealed the most promising fragment with a dissociation constant of 0.3±0.1 mM and a ligand efficiency of 0.3 kcal mol-1HA-1, which affected the orthosteric site. This effect was substantiated by site-directed mutagenesis in the orthosteric and secondary pockets. Future drug-discovery campaigns that aim to develop small molecule inhibitors can benefit from allosteric sites in lectins as a new therapeutic approach against antibiotic-resistant pathogens

Domaines: Chimie thérapeutique

Elena Shanina, Sakonwan Kuhaudomlarp, Kanhaya Lal, Peter Seeberger, Anne Imberty, et al.. Druggable allosteric sites in β‐propeller lectins. Angewandte Chemie International Edition, 2021, ⟨10.1002/anie.202109339⟩. ⟨hal-03412507⟩