A Gut-Restricted Lithocholic Acid Analog as an Inhibitor of Gut Bacterial Bile Salt Hydrolases.
A Gut-Restricted Lithocholic Acid Analog as an Inhibitor of Gut Bacterial Bile Salt Hydrolases.
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肠道限制性石胆酸类似物作为肠道细菌胆盐水解酶抑制剂。
DOI：
10.1021/acschembio.1c00192
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发表时间：
2021-08-20
影响因子：
4
通讯作者：
Devlin, A. Sloan
中科院分区：
文献类型：
--
作者：
Adhikari, Arijit A.;Ramachandran, Deepti;Chaudhari, Snehal N.;Powell, Chelsea E.;Li, Wei;McCurry, Megan D.;Banks, Alexander S.;Devlin, A. Sloan
胆汁酸既是帮助消化的清洁剂，又是与宿主受体结合的信号分子，在宿主生理中发挥着至关重要的作用。肠道细菌胆盐水解酶(BSH)执行门户反应，导致宿主产生的初级胆汁酸转化为细菌修饰的次级胆汁酸。针对BSHS的小分子探针将有助于阐明这些代谢物在宿主生理中的因果作用。我们之前报道了一种低肠道通透性的共价BSH抑制剂的开发。在这里，我们以我们以前的发现为基础，描述了第二代肠道限制性BSH抑制剂的开发，该抑制剂具有增强的效力、减少的非靶向效应和持久的体内疗效。以胆汁酸为核心的构效关系(SAR)研究确定了一种化合物AAA-10，它含有C3磺化的石胆酸支架和α-氟甲基酮弹头，是一种有效的泛BSH抑制剂。该化合物抑制小鼠和人类粪便浆液、细菌培养和纯化的BSH蛋白中的BSH活性，并且与第一代化合物相比，对哺乳动物细胞的毒性降低。野生型小鼠口服AAA-10 5天后，胃肠道内次级胆汁酸脱氧胆酸(DCA)和胆石酸(LCA)丰度降低，全身暴露AAA-10较低，表明AAA-10是体内抑制BSH活性和调节胆酸库组成的有效工具。
Bile acids play crucial roles in host physiology by acting as both detergents that aid in digestion and as signaling molecules that bind to host receptors. Gut bacterial bile salt hydrolase (BSH) enzymes perform the gateway reaction leading to the conversion of host-produced primary bile acids into bacterially modified secondary bile acids. Small molecule probes that target BSHs will help elucidate the causal roles of these metabolites in host physiology. We previously reported the development of a covalent BSH inhibitor with low gut permeability. Here, we build on our previous findings and describe the development of a second-generation gut-restricted BSH inhibitor with enhanced potency, reduced off-target effects, and durable in vivo efficacy. Structure-activity relationship (SAR) studies focused on the bile acid core identified a compound, AAA-10, containing a C3-sulfonated lithocholic acid scaffold and an alpha-fluoromethyl ketone warhead as a potent pan-BSH inhibitor. This compound inhibits BSH activity in mouse and human fecal slurry, bacterial cultures, and purified BSH proteins and displays reduced toxicity against mammalian cells compared to first generation compounds. Oral administration of AAA-10 to wild-type mice for 5 days resulted in a decrease in the abundance of the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA) in the mouse GI tract with low systemic exposure of AAA-10, demonstrating that AAA-10 is an effective tool for inhibiting BSH activity and modulating bile acid pool composition in vivo.
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影响因子：
29
作者：
Ellacott KL;Morton GJ;Woods SC;Tso P;Schwartz MW
通讯作者：
Schwartz MW
肠道选择性法尼醇 X 受体抑制可改善肥胖相关的代谢功能障碍。
影响因子：
16.6
作者：
Jiang C;Xie C;Lv Y;Li J;Krausz KW;Shi J;Brocker CN;Desai D;Amin SG;Bisson WH;Liu Y;Gavrilova O;Patterson AD;Gonzalez FJ
通讯作者：
Gonzalez FJ
影响因子：
3.2
作者：
Ferruzza, Simonetta;Rossi, Carlotta;Sambuy, Yula
通讯作者：
Sambuy, Yula
影响因子：
18.2
作者：
Parasar, Bibudlia;Zhou, Hao;Chang, Pamela, V
通讯作者：
Chang, Pamela, V
影响因子：
14.8
作者：
Adhikari, Arijit A.;Seegar, Tom C. M.;Devlin, A. Sloan
通讯作者：
Devlin, A. Sloan