Development of multifunctional pyrrole-imidazole polyamides that increase hepatocyte growth factor and suppress transforming growth factor-81

作者全名："Chen, Lan; Fukuda, Noboru; Ueno, Takahiro; Abe, Masanori; Matsumoto, Taro"

作者地址："[Chen, Lan; Fukuda, Noboru; Matsumoto, Taro] Nihon Univ, Sch Med, Dept Funct Morphol, Div Cell Regenerat & Transplantat, Tokyo 1738610, Japan; [Chen, Lan] Chongqing Med Univ, Dept Gen Med, Childrens Hosp, Chongqing 400000, Peoples R China; [Fukuda, Noboru; Ueno, Takahiro; Abe, Masanori] Nihon Univ, Sch Med, Dept Internal Med, Div Nephrol Hypertens & Endocrinol, Tokyo 1738610, Japan"

通信作者："Fukuda, N (通讯作者)，Nihon Univ, Sch Med, Dept Funct Morphol, Div Cell Regenerat & Transplantat, Tokyo 1738610, Japan."

来源：JOURNAL OF PHARMACOLOGICAL SCIENCES

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001133750600001

JCR分区：Q2

影响因子：3.5

年份：2024

卷号：154

期号：1

开始页：1

结束页：8

文献类型：Article

关键词：Pyrrole-imidazole polyamide; Hepatocyte growth factor; Transforming growth factor-81; Multifunctional; Fibrotic disease

摘要："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 poly-amides that increase hepatocyte growth factor (HGF) and decrease transforming growth factor (TGF)-81.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 poly-amides that increase HGF and suppress TGF-81 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-81 mRNA expression in HDFs stimulated by phorbol 12-myristate 13-acetate. HGF-2 and HGF-4 significantly inhibited the TGF-81 protein expression in HDFs with siRNA targeting HGF, indicating that HGF-2 and HGF-4 directly inhibited the expression of TGF-81.Conclusion: The designed and synthetic HGF PI polyamides targeting the HGF promoter, which increased the expression of HGF and suppressed the expression of TGF-8, will be a potential practical medicine for fibrotic diseases, including progressive renal diseases."

基金机构：JSPS KAKENHI [20K08599]

基金资助正文：This study was supported by JSPS KAKENHI Grant Number 20K08599 (2020-2022).