Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.
Department of Chemistry, National Taiwan University, Taipei, Taiwan.
Commun Biol. 2021 Mar 4;4(1):280. doi: 10.1038/s42003-021-01815-w.
Irinotecan inhibits cell proliferation and thus is used for the primary treatment of colorectal cancer. Metabolism of irinotecan involves incorporation of β-glucuronic acid to facilitate excretion. During transit of the glucuronidated product through the gastrointestinal tract, an induced upregulation of gut microbial β-glucuronidase (GUS) activity may cause severe diarrhea and thus force many patients to stop treatment. We herein report the development of uronic isofagomine (UIFG) derivatives that act as general, potent inhibitors of bacterial GUSs, especially those of Escherichia coli and Clostridium perfringens. The best inhibitor, C6-nonyl UIFG, is 23,300-fold more selective for E. coli GUS than for human GUS (K = 0.0045 and 105 μM, respectively). Structural evidence indicated that the loss of coordinated water molecules, with the consequent increase in entropy, contributes to the high affinity and selectivity for bacterial GUSs. The inhibitors also effectively reduced irinotecan-induced diarrhea in mice without damaging intestinal epithelial cells.
伊立替康抑制细胞增殖，因此被用于结直肠癌的主要治疗。伊立替康的代谢涉及β-葡萄糖醛酸的掺入，以促进排泄。在葡萄糖醛酸化产物通过胃肠道的过程中，肠道微生物β-葡萄糖醛酸酶（GUS）活性的诱导上调可能导致严重腹泻，从而迫使许多患者停止治疗。我们在此报告了尿嘧啶异野尻霉素（UIFG）衍生物的开发，它们是细菌 GUS 的通用、强效抑制剂，特别是大肠杆菌和产气荚膜梭菌的 GUS。最好的抑制剂是 C6-壬基 UIFG，对大肠杆菌 GUS 的选择性比人 GUS 高 23300 倍（K=0.0045 和 105 μM，分别）。结构证据表明，配位水分子的丧失，以及随之而来的熵增加，有助于对细菌 GUS 具有高亲和力和选择性。抑制剂还能有效减少小鼠中伊立替康引起的腹泻，而不损害肠上皮细胞。
