Статья

Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity

Hsien‐Ya LinDepartment of Chemistry, National Taiwan University, Taipei, TaiwanChia-Yu ChenDepartment of Chemistry, National Taiwan University, Taipei, TaiwanTing‐Chien LinDepartment of Chemistry, National Taiwan University, Taipei, TaiwanLun-Fu YehInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanWei‐Che HsiehInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanShijay GaoInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanPierre‐Alain BurnoufInstitute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanBing‐Mae ChenInstitute of Biomedical Sciences, Academia Sinica, Taipei, TaiwanTung-Ju HsiehInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanP. DashnyamInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanYen-Hsi KuoInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanZhijay TuInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanSteve R. RofflerGraduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. [email protected]Chun‐Hung LinDepartment of Chemistry, National Taiwan University, Taipei, Taiwan. [email protected]

2021en

ABI

Аннотация

Abstract 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 i = 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.

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Идентификаторы

DOI: 10.1038/s42003-021-01815-w

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