CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
J Med Chem. 2012 Mar 22;55(6):2702-10. doi: 10.1021/jm201570s. Epub 2012 Mar 8.
Shiga toxin (Stx)-producing Escherichia coli (STEC) causes diarrhea and colitis in humans that can develop into a life-threatening hemolytic uremic syndrome (HUS). Developing efficient means of controlling STEC diseases, for which no drugs or vaccines are currently available, remains a high priority. We report here the construction and development of chitosan conjugates bearing the Stx ligand trisaccharide globotriose to demonstrate their potential as STEC disease treatment agents. The synthesis was accomplished by grafting a globotriose derivative containing an aldehyde-functionalized aglycone to chitosan amino groups. The obtained globotriose-chitosan conjugate bound with high affinity to Stx and efficiently neutralized its toxicity on Vero cells. Moreover, Stx levels in the gut of infected mice receiving oral doses of the conjugate were greatly diminished, enabling the mice to resist a fatal STEC challenge. The conjugate appears to function as a Stx adsorbent in the gut, preventing toxin entry into the bloodstream and consequent development of HUS. As such, the conjugate could act as a novel agent against STEC disease.
产志贺毒素大肠杆菌（STEC）可引起人类腹泻和结肠炎，严重时可发展为危及生命的溶血性尿毒综合征（HUS）。目前尚无针对 STEC 疾病的有效治疗方法，因此开发这类疾病的治疗方法仍然是当务之急。本研究构建了携带 Stx 配体三糖神经节苷脂的壳聚糖缀合物，并证明其具有作为 STEC 疾病治疗剂的潜力。该合成通过将含有醛基化非糖部分的神经节苷脂衍生物接枝到壳聚糖的氨基上完成。所得神经节苷脂-壳聚糖缀合物与 Stx 具有高亲和力，并能有效中和其对 Vero 细胞的毒性。此外，接受口服缀合物的感染小鼠肠道中的 Stx 水平大大降低，使它们能够抵抗致命的 STEC 挑战。该缀合物似乎在肠道中作为 Stx 的吸附剂发挥作用，防止毒素进入血液，从而避免 HUS 的发生。因此，该缀合物可作为一种针对 STEC 疾病的新型治疗药物。
