Institute of Biological Chemistry, Academia Sinica, No 128, Academia Road, Taipei 11529, Taiwan.
Molecular and Biological Agricultural Sciences, Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan.
J Med Chem. 2020 May 14;63(9):4617-4627. doi: 10.1021/acs.jmedchem.9b01918. Epub 2020 Mar 9.
Selective inhibitors of gut bacterial β-glucuronidases (GUSs) are of particular interest in the prevention of xenobiotic-induced toxicities. This study reports the first structure-activity relationships on potency and selectivity of several iminocyclitols (-) for the GUSs. Complex structures of GUS with - explained how charge, conformation, and substituent of iminocyclitols affect their potency and selectivity. N1 of uronic isofagomine () made strong electrostatic interactions with two catalytic glutamates of GUSs, resulting in the most potent inhibition ( ≥ 11 nM). C6-propyl analogue of () displayed 700-fold selectivity for opportunistic bacterial GUSs ( = 74 nM for GUS and 51.8 μM for GUS). In comparison with , there was 200-fold enhancement in the selectivity, which was attributed to differential interactions between the propyl group and loop 5 residues of the GUSs. The results provide useful insights to develop potent and selective inhibitors for undesired GUSs.
选择性肠道细菌β-葡萄糖醛酸酶（GUS）抑制剂在预防外源性物质诱导的毒性方面具有特别的意义。本研究报告了几种异环糖醇（-）对 GUS 的活性和选择性的首个结构-活性关系。GUS 与 -的复合物结构解释了电荷、构象和取代基如何影响它们的活性和选择性。异鼠李糖（）的尿嘧啶 N1 与 GUS 的两个催化谷氨酸形成强静电相互作用，导致最强的抑制作用（≥11 nM）。（）的 C6-丙基类似物对机会性细菌 GUS 具有 700 倍的选择性（对 GUS 的 = 74 nM，对 GUS 的 51.8 μM）。与相比，选择性提高了 200 倍，这归因于丙基和 GUS 环 5 残基之间的差异相互作用。这些结果为开发针对非所需 GUS 的有效且选择性抑制剂提供了有用的见解。
