Department of Chemical Biology & Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands.
J Med Chem. 2021 May 13;64(9):6059-6069. doi: 10.1021/acs.jmedchem.1c00152. Epub 2021 Apr 28.
Shiga toxin is an AB toxin produced by species, while related toxins are produced by Shiga toxin-producing (STEC). Infection by Shigella can lead to bloody diarrhea followed by the often fatal hemolytic uremic syndrome (HUS). In the present paper, we aimed for a simple and effective toxin inhibitor by comparing three classes of carbohydrate-based inhibitors: glycodendrimers, glycopolymers, and oligosaccharides. We observed a clear enhancement in potency for multivalent inhibitors, with the divalent and tetravalent compounds inhibiting in the millimolar and micromolar range, respectively. However, the polymeric inhibitor based on galabiose was the most potent in the series exhibiting nanomolar inhibition. Alginate and chitosan oligosaccharides also inhibit Shiga toxin and may be used as a prophylactic drug during shigella outbreaks.
志贺毒素是由 种产生的 AB 毒素，而相关毒素则由产志贺毒素的 （STEC）产生。志贺氏菌感染可导致血性腹泻，随后常发生致命性溶血性尿毒综合征（HUS）。在本研究中，我们通过比较三类基于碳水化合物的抑制剂：糖树状聚合物、糖聚合物和寡糖，旨在寻找一种简单有效的毒素抑制剂。我们观察到多价抑制剂的效力明显增强，二价和四价化合物的抑制作用分别在毫摩尔和微摩尔范围内。然而，基于半乳糖的聚合物抑制剂在该系列中具有最强的抑制作用，其抑制作用达到纳摩尔级。藻酸盐和壳聚糖寡糖也能抑制志贺毒素，可在志贺氏菌爆发期间用作预防性药物。
