TY - JOUR
T1 - Entropy-driven binding of gut bacterial β-glucuronidase inhibitors ameliorates irinotecan-induced toxicity
AU - Lin, Hsien Ya
AU - Chen, Chia Yu
AU - Lin, Ting Chien
AU - Yeh, Lun Fu
AU - Hsieh, Wei Che
AU - Gao, Shijay
AU - Burnouf, Pierre Alain
AU - Chen, Bing Mae
AU - Hsieh, Tung Ju
AU - Dashnyam, Punsaldulam
AU - Kuo, Yen Hsi
AU - Tu, Zhijay
AU - Roffler, Steve R.
AU - Lin, Chun Hung
N1 - Funding Information:
This work was supported by the Summit Project at Academia Sinica (AS-SUMMIT-109 and AS-KPQ-109-BioMed) and the Ministry of Science and Technology (MOST-108-3114-Y-001-002), Taiwan. We thank Drs. Chris Jao and Meng-Ru Ho of the Biophysics Core Facility for technical assistance with the thermodynamics experiments, Ms. Hui-Ling Shi of the National Core Facility for protein crystallization screening, and the beamlines of the National Synchrotron Radiation Research Center (Taiwan) for X-ray diffraction and data collection.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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 (Ki = 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.
AB - 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 (Ki = 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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U2 - 10.1038/s42003-021-01815-w
DO - 10.1038/s42003-021-01815-w
M3 - Article
C2 - 33664385
AN - SCOPUS:85102118649
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 280
ER -