A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis.
A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis.
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DOI：
10.1126/scitranslmed.abn7491
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发表时间：
2023-08-09
影响因子：
17.1
通讯作者：
Slusher, Barbara S. S.
中科院分区：
文献类型：
--
作者：
Peters, Diane E. E.;Norris, Lauren D. D.;Tenora, Lukas;Snajdr, Ivan;Ponti, Andras K.;Zhu, Xiaolei;Sakamoto, Shinji;Veeravalli, Vijayabhaskar;Pradhan, Manisha;Alt, Jesse;Thomas, Ajit G. G.;Majer, Pavel;Rais, Rana;McDonald, Christine;Slusher, Barbara S. S.
目前迫切需要开发炎症性肠病(IBD)的治疗方法，因为高达40%的中到重度IBD患者无法用现有药物充分控制。谷氨酸羧肽酶II(GCPII)已成为一种很有前途的治疗靶点。这种酶在正常回肠和结肠中表达最低，但在IBD患者和临床前结肠炎模型的活检组织中显著上调。在这里，我们产生了一类GCPII抑制剂，旨在限制肠道口服给药，并使用体外和体内模型询问疗效和机制。铅抑制物(S)-IBD3540对急性和慢性啮齿动物结肠炎模型均有效(半数最大抑制浓度为4纳摩尔)、选择性强、肠道受限(小鼠结肠炎AUC结肠/血浆50)。在葡聚糖硫酸钠诱导的结肠炎中，口服(S)-IBD3540可抑制75%的结肠GCPII活性，并呈剂量依赖性地改善大体和组织学疾病，并显著减轻单核细胞炎症。在白介素10(IL-10)基因敲除小鼠的自发性结肠炎中，在疾病发作后开始每日一次口服(S)-IBD3540，改善了疾病，恢复了结肠组织学，并通过粪便Lipocalin 2和结肠促炎症细胞因子/趋化因子，包括肿瘤坏死因子-α和IL-17的减少得到了证明。利用原代人结肠上皮气-液界面单分子层研究其机制，我们进一步发现(S)-IBD3540通过降低屏障通透性，使紧密连接蛋白表达正常化，并减少原天冬氨酸氨基转移酶-3的激活，对浸水所致的氧化应激损伤具有保护作用。综上所述，这项工作表明，使用肠道限制性、口服活性的小分子(S)-IBD3540局部抑制肠道GCPII是治疗IBD的一种有前景的方法。
There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUCcolon/plasma > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium–induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor–α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.
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影响因子：
3.7
作者：
Chassaing B;Srinivasan G;Delgado MA;Young AN;Gewirtz AT;Vijay-Kumar M
通讯作者：
Vijay-Kumar M
一类重要的微生物胆汁酸的生物合成途径。
影响因子：
14.8
作者：
Devlin AS;Fischbach MA
通讯作者：
Fischbach MA
影响因子：
4.9
作者：
De Vries, L. C. S.;Duarte, J. M.;Wildenberg, M. E.
通讯作者：
Wildenberg, M. E.
DOI：
10.1073/pnas.1423221112
发表时间：
2015-02-24
影响因子：
11.1
作者：
Baldwin, Katherine T.;Carbajal, Kevin S.;Giger, Roman J.
通讯作者：
Giger, Roman J.
DOI：
10.1097/meg.0000000000000378
发表时间：
2015-07-01
影响因子：
2.1
作者：
Gordon, Jason P.;McEwan, Phil C.;Puelles, Jorge
通讯作者：
Puelles, Jorge