Development of multifunctional pyrrole-imidazole polyamides that increase hepatocyte growth factor and suppress transforming growth factor-β1

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of pharmacological sciences Pub Date : 2023-11-19 DOI:10.1016/j.jphs.2023.11.001

Lan Chen , Noboru Fukuda , Takahiro Ueno , Masanori Abe , Taro Matsumoto

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引用次数: 0

Abstract

Purpose

The DNA recognition peptide compounds pyrrole-imidazole (PI) polyamides bind to the minor groove and can block the binding of transcription factors to target sequences. To develop more PI polyamides as potential treatments for fibrotic diseases, including chronic renal failure, we developed multifunctional PI polyamides that increase hepatocyte growth factor (HGF) and decrease transforming growth factor (TGF)-β1.

Methods

We designed seven PI polyamides (HGF-1 to HGF-7) that bind to the chicken ovalbumin upstream promoter transcription factor-1 (COUP-TF1) binding site of the HGF promoter sequence. We selected PI polyamides that increase HGF and suppress TGF-β1 in human dermal fibroblasts (HDFs).

Findings

Gel shift assays showed that HGF-2 and HGF-4 bound the appropriate dsDNAs. HGF-2 and HGF-4 significantly inhibited the TGF-β1 mRNA expression in HDFs stimulated by phorbol 12-myristate 13-acetate. HGF-2 and HGF-4 significantly inhibited the TGF-β1 protein expression in HDFs with siRNA targeting HGF, indicating that HGF-2 and HGF-4 directly inhibited the expression of TGF-β1.

Conclusion

The designed and synthetic HGF PI polyamides targeting the HGF promoter, which increased the expression of HGF and suppressed the expression of TGF-β, will be a potential practical medicine for fibrotic diseases, including progressive renal diseases.

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增加肝细胞生长因子和抑制转化生长因子-β1的多功能吡咯-咪唑聚酰胺的研制

目的DNA识别肽化合物吡咯-咪唑(PI)聚酰胺结合在小凹槽上，可以阻断转录因子与靶序列的结合。为了开发更多的PI聚酰胺作为纤维化疾病(包括慢性肾衰竭)的潜在治疗方法，我们开发了可增加肝细胞生长因子(HGF)和降低转化生长因子(TGF)-β1的多功能PI聚酰胺。方法设计7种结合鸡卵白蛋白上游启动子转录因子-1 (COUP-TF1)结合位点的PI聚酰胺(HGF-1 ~ HGF-7)。我们选择的PI聚酰胺可以增加人真皮成纤维细胞(HDFs)中的HGF并抑制TGF-β1。凝胶移位实验显示HGF-2和HGF-4结合了合适的dna。HGF-2和HGF-4显著抑制12-肉豆蔻酸13-乙酸佛波刺激HDFs中TGF-β1 mRNA的表达。HGF-2和HGF-4用靶向HGF的siRNA显著抑制了TGF-β1蛋白在HDFs中的表达，说明HGF-2和HGF-4直接抑制了TGF-β1的表达。结论设计合成的靶向HGF启动子的HGF PI聚酰胺可提高HGF的表达，抑制TGF-β的表达，有望成为治疗包括进行性肾脏疾病在内的纤维化疾病的潜在实用药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of pharmacological sciences 医学-药学

CiteScore

6.20

自引率

2.90%

发文量

104

审稿时长

31 days

期刊介绍： Journal of Pharmacological Sciences (JPS) is an international open access journal intended for the advancement of pharmacological sciences in the world. The Journal welcomes submissions in all fields of experimental and clinical pharmacology, including neuroscience, and biochemical, cellular, and molecular pharmacology for publication as Reviews, Full Papers or Short Communications. Short Communications are short research article intended to provide novel and exciting pharmacological findings. Manuscripts concerning descriptive case reports, pharmacokinetic and pharmacodynamic studies without pharmacological mechanism and dose-response determinations are not acceptable and will be rejected without peer review. The ethnopharmacological studies are also out of the scope of this journal. Furthermore, JPS does not publish work on the actions of biological extracts unknown chemical composition.