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

Hsien-Ya Lin, Chia-Yu Chen, Ting-Chien Lin and colleagues perform structure-guided modifications of the compound uronic isofagomaine in order to engineer a highly specific and potent inhibitor of gut bacterial β-glucuronidases (GUSs). The authors present eight crystal structures and demonstrate in vivo efficacy of the optimised C6-alkyl derivative inhibitor in mice models. This study may enhance the development of inhibitors of microbial GUS for use in colorectal cancer therapy to minimize the undesired side effects of irinotecan treatment.