Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

Takagi, Keiko; Midorikawa, Yutaka; Takayama, Tadatoshi; Fujiwara, Kyoko; Soma, Masayoshi; Nagase, Hiroki; Miki, Toshio; Fukuda, Noboru

doi:10.3390/molecules25122883

Cited by 3 publications

(3 citation statements)

References 45 publications

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“…In particular, an immunohistochemical study revealed a complete inhibition of TGF-β1 staining in the medulla of the kidneys of marmosets. In subsequent studies, the inhibitory effect of PI polyamide on the synthesis of TGF-β1 in diabetic nephropathy 18 and in liver and lung cancer cells 19 was confirmed. Thus, the researchers proved the selectivity and efficiency of the structure they designed.…”

Section: Discussionmentioning

confidence: 83%

In silico study of HASDI (high-affinity selective DNA intercalator) as a new agent capable of highly selective recognition of the DNA sequence

Zaremba

Zahorodnia

2023

Sci Rep

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Cancer as an acquired genetic disease is based on changes both in the genome itself and in transcription processes. Accordingly, it is at the DNA level that it makes sense to search for and design agents capable of effective and selective anticancer action. In this study, we used an iterative approach based on a molecular dynamics simulation to design a highly selective DNA-intercalating agent called HASDI. To confirm its selective affinity to DNA, we conducted two simulation experiments: HASDI in a complex with a DNA fragment of the EBNA1 gene (it targets 16 nucleotide pairs of this gene) and HASDI in a complex with a random DNA fragment of the KCNH2 gene. The molecular dynamics simulation was carried out in the GROMACS 2019 package. The binding energy was calculated by gmx_MMPBSA 1.5.2. The further analysis was performed using the built-in utilities of GROMACS, gmx_MMPBSA and also XMGRACE and Pymol 1.8. As a result, we determined that the EBNA1-50nt/HASDI complex was stable throughout the whole simulation trajectory. HASDI, due to the presence of a linker modified depending on a specific pair of nitrogenous bases, formed an average of 32 hydrogen bonds with a sequence of 16 nucleotide pairs. Phenazine rings were stably intercalated every 2 base pairs. The root-mean-square deviation of HASDI in such a complex fluctuated around the value of 6.5 Å and had no tendency to increase. The calculated value of the binding free energy was − 235.3 ± 7.77 kcal/mol. The KCNH2-50nt/HASDI complex, as an example of the intercalation of the designed structure into a random part of the human genome, maintained the stability of its position at a level comparable to the EBNA1-50nt/HASDI complex. The phenazine rings were constantly intercalated in their original positions, and the root-mean-square deviation fluctuated around one value, although it had a tendency to chaotic changes. At the same time, this complex was characterized by 17–19 hydrogen bonds, on average, and the binding free energy was − 193.47 ± 14.09 kcal/mol. Moreover, the DNA duplex had local single-nucleotide melting in the region of the 4th linker. According to a significant decrease in the number of hydrogen bonds, a decrease in energy gain, as well as a decrease in the stability of the DNA duplex characteristic of the KCNH2-50nt/HASDI complex compared to the target EBNA1-50nt/HASDI complex, the molecule we designed can be considered a potentially selective DNA polyintercalating agent capable of relatively accurate recognition of 16 base pairs.

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Section: Discussionmentioning

confidence: 83%

In silico study of HASDI (high-affinity selective DNA intercalator) as a new agent capable of highly selective recognition of the DNA sequence

Zaremba

Zahorodnia

2023

Sci Rep

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“…46 TGF-β is involved in tumorigenesis. 47 Thus, the similarity may due to various functions of TGF-β.…”

Section: Discussionmentioning

confidence: 99%

<p>LncRNA PVT1 Suppresses the Progression of Renal Fibrosis via Inactivation of TGF-β Signaling Pathway</p>

Cao

Qin

Zhang

et al. 2020

DDDT

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Background: Renal fibrosis is a frequent pathway leading to end-stage kidney dysfunction. In addition, renal fibrosis is the ultimate manifestation of chronic kidney diseases (CKD). Long noncoding RNAs (lncRNAs) are known to be involved in occurrence of renal fibrosis, and lncRNA plasmacytoma variant translocation 1 (PVT1) has been reported to act as a key biomarker in renal diseases. However, the role of PVT1 in renal fibrosis remains unclear. Materials and Methods: HK-2 cells were treated with TGF-β1 to mimic renal fibrosis in vitro. Gene and protein expressions in HK-2 cells were measured by qRT-PCR and Western-blot, respectively. ELISA was used to test the level of creatinine (CR) and blood urea nitrogen (BUN) in serum of mice. Additionally, unilateral ureteral obstruction (UUO)-induced renal fibrosis mice model was established to investigate the effect of PVT1 on renal fibrosis in vivo. Results: PVT1 was upregulated in TGF-β1-treated HK-2 cells. In addition, TGF-β1-induced upregulation of α-SMA and fibronectin in HK-2 cells was significantly reversed by PVT1 knockdown. Meanwhile, PVT1 bound to miR-181a-5p in HK-2 cells. Moreover, miR-181a-5p directly targeted TGF-βR1. Furthermore, miR-181a-5p antagonist could significantly reverse the antifibrotic effect of PVT1 knockdown. Besides, knockdown of PVT1 notably attenuated the symptom of renal fibrosis in vivo. Conclusion: Knockdown of PVT1 significantly inhibited the progression of renal fibrosis in vitro and in vivo. Thus, PVT1 may serve as a potential target for the treatment of renal fibrosis.

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“…Takagi et al. (2020) 89 also examined the effects of the PIP targeting human TGF‐β1 on the malignant phenotypes of liver cancer cells, which showed suppression in the migration and invasion of liver cancer cells and reduction in TGF‐β1‐induced epithelial‐mesenchymal transition, and in vivo tumor growth inhibition. Otsuki et al.…”

Section: Designing Pips To Modulate Diverse Transcriptional Targetsmentioning

confidence: 99%

Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation

Bai,

Ziadlou,

Vaijayanthi

et al. 2023

Allergy

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Transcription therapy is an emerging approach that centers on identifying the factors associated with the malfunctioning gene transcription machinery that causes diseases and controlling them with designer agents. Until now, the primary research focus in therapeutic gene modulation has been on small‐molecule drugs that target epigenetic enzymes and critical signaling pathways. However, nucleic acid‐based small molecules have gained popularity in recent years for their amenability to be pre‐designed and realize operative control over the dynamic transcription machinery that governs how the immune system responds to diseases. Pyrrole–imidazole polyamides (PIPs) are well‐established DNA‐based small‐molecule gene regulators that overcome the limitations of their conventional counterparts owing to their sequence‐targeted specificity, versatile regulatory efficiency, and biocompatibility. Here, we emphasize the rational design of PIPs, their functional mechanisms, and their potential as targeted transcription therapeutics for disease treatment by regulating the immune response. Furthermore, we also discuss the challenges and foresight of this approach in personalized immunotherapy in precision medicine.

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Effects of Pyrrole-Imidazole Polyamides Targeting Human TGF-β1 on the Malignant Phenotypes of Liver Cancer Cells

Cited by 3 publications

References 45 publications

In silico study of HASDI (high-affinity selective DNA intercalator) as a new agent capable of highly selective recognition of the DNA sequence

In silico study of HASDI (high-affinity selective DNA intercalator) as a new agent capable of highly selective recognition of the DNA sequence

<p>LncRNA PVT1 Suppresses the Progression of Renal Fibrosis via Inactivation of TGF-β Signaling Pathway</p>

Nucleic acid‐based small molecules as targeted transcription therapeutics for immunoregulation

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