Carbohydrate binding proteins are therapeutic targets because of their key role in host-pathogen recognition and cell-to-cell communication. Unfortunately, the hydrophilic nature of the carbohydrate binding pockets is the main obstacle in inhibitor design. In this work, we addressed this challenge by screening fragment library to uncover metal-binding compounds as a novel group of compounds that target calcium-dependent carbohydrate binding proteins such as those from pathogens (LecA, LecB) and mammals (DC-SIGN and Langerin). Crystal structure of a complex between LecA and an identified compound, hydroxamate, illustrated the selectivity of the compound for LecA. All together, this work uncovers a new class of compounds that set a stepping stone for future drug discovery campaign for these difficult therapeutic protein targets.
Shanina E, Kuhaudomlarp S, Siebs E, Fuchberger FF, Denis M, da Silva Figueiredo Celestino Gomes P, Clausen MH, Seeberger PH, Rognan D, Titz A, Imberty A, Rademacher C. Targeting undruggable carbohydrate recognition sites through focused fragment library design. Communications Chemistry. 2022;5:64
|Dr. Sakonwan Kuhaudomlarp