Design and evaluation of IKK-activated GSK3β inhibitory peptide as an inflammation-responsive anti-colitic therapeutic,Biomaterials Science

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Design and evaluation of IKK-activated GSK3β inhibitory peptide as an inflammation-responsive anti-colitic therapeutic
Biomaterials Science ( IF 5.8 ) Pub Date : 2021-08-16 , DOI: 10.1039/d1bm00533b
Sungchae Hong ₁ , Sanghyun Ju ₁ , Jin-Wook Yoo ₁ , Nam-Chul Ha ₂ , Yunjin Jung ₁

Affiliation

Glycogen synthase kinase-3β (GSK3β), a multi-functional kinase, is a promising therapeutic target for the treatment of inflammation. Inhibitory κB kinase (IKK)-activated GSK3β inhibitory peptide (IAGIP) was designed as an inflammation-responsive anti-colitic therapeutic. To optimize therapeutic efficiency, IAGIP was tested using two different drug delivery techniques: colon-targeted delivery and cell-permeable peptide modification. In cell-based experiments, in response to tumor necrosis factor (TNF)- and lipopolysaccharide (LPS)-mediated activation of IKK, cell-permeable IAGIP (CTP-IAGIP) inhibited GSK3β, leading to increased production of anti-inflammatory cytokine interleukin-10 (IL-10) and suppression of TNF- and LPS-induced NFκB activity. Oral gavage of CTP-IAGIP loaded in the colon-targeted capsule attenuated 2,4,6-trinitrobenzene sulfonic acid-induced rat colitis and lowered the expression levels of NFκB-regulated proteins in the inflamed colons. CTP-IAGIP further induced IL-10 production in the inflamed colonic tissues; however, the levels of IL-10 were not affected in the normal colonic tissue or colonic tissue in which inflammation had subsided. Collectively, our data suggest that IAGIP administered using the aforementioned drug delivery techniques is an orally active anti-colitic drug selectively responding to inflammation.

中文翻译：

IKK 激活的 GSK3β 抑制肽作为炎症反应性抗结肠炎治疗剂的设计和评估

糖原合酶激酶-3β (GSK3β) 是一种多功能激酶，是治疗炎症的有前途的治疗靶点。抑制性 κB 激酶 (IKK) 激活的 GSK3β 抑制肽 (IAGIP) 被设计为一种炎症反应性抗结肠炎治疗剂。为了优化治疗效率，IAGIP 使用两种不同的药物递送技术进行了测试：结肠靶向递送和细胞渗透性肽修饰。在基于细胞的实验中，为了响应肿瘤坏死因子 (TNF) 和脂多糖 (LPS) 介导的 IKK 激活，细胞渗透性 IAGIP (CTP-IAGIP) 抑制 GSK3β，导致抗炎细胞因子白细胞介素的产生增加。 10 (IL-10) 和抑制 TNF- 和 LPS 诱导的 NFκB 活性。结肠靶向胶囊中装载的 CTP-IAGIP 的口服管饲减弱了 2,4，6-三硝基苯磺酸诱导的大鼠结肠炎并降低发炎结肠中 NFκB 调节蛋白的表达水平。CTP-IAGIP 进一步诱导发炎结肠组织中 IL-10 的产生；然而，IL-10 的水平在正常结肠组织或炎症消退的结肠组织中没有受到影响。总的来说，我们的数据表明，使用上述药物递送技术施用的 IAGIP 是一种口服活性抗结肠炎药物，对炎症有选择性的反应。

更新日期：2021-09-01

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