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Non‐Carbohydrate Glycomimetics as Inhibitors of Calcium(II)‐binding Lectins

Abstract : Because of the antimicrobial resistance crisis, lectins are considered novel drug targets. Pseudomonas aeruginosa utilizes LecA and LecB in the infection process. Inhibition of both lectins with carbohydrate-derived molecules can reduce biofilm formation to restore antimicrobial susceptibility. Here, we focused on non-carbohydrate inhibitors for LecA to explore new avenues for lectin inhibition. From a screening cascade we obtained one experimentally confirmed hit, a catechol, belonging to the well-known PAINS compounds. Rigorous analyses validated electron-deficient catechols as millimolar LecA inhibitors. The first co-crystal structure of a non-carbohydrate inhibitor in complex with a bacterial lectin clearly demonstrates the catechol mimicking the binding of natural glycosides with LecA. Importantly, catechol 3 is the first non-carbohydrate lectin ligand that binds bacterial and mammalian calcium(II)-binding lectins, giving rise to this fundamentally new class of glycomimetics.
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https://hal.archives-ouvertes.fr/hal-03083693
Contributor : Anne Imberty <>
Submitted on : Thursday, March 4, 2021 - 9:24:46 AM
Last modification on : Wednesday, September 22, 2021 - 9:14:05 AM

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Sakonwan Kuhaudomlarp, Eike Siebs, Elena Shanina, Jérémie Topin, Ines Joachim, et al.. Non‐Carbohydrate Glycomimetics as Inhibitors of Calcium(II)‐binding Lectins. Angewandte Chemie International Edition, Wiley-VCH Verlag, 2021, 60, pp.2-13. ⟨10.1002/anie.202013217⟩. ⟨hal-03083693v2⟩

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