Assessment of the effectiveness of the peptide inhibitor homologous to the transforming growth factor β cytokine blocking the TGFβRI/TGFβRII receptor complex—pilot study

IF 4.6 2区 医学 Q2 ALLERGY
Marynowski Mateusz, Karbownik Michał Seweryn, Szemraj Janusz, Kuna Piotr, Michał Gabriel Panek
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引用次数: 0

Abstract

Background

A key player in the fibrotic process is the transforming growth factor β (TGF-β) which enhances extracellular matrix production by increasing the transcription of matrix proteins. The cytokine TGF-β first binds to the TGFβRII receptor (dimer), resulting in the recruitment of the TGFβRI receptor (dimer). The complex thus formed leads to the phosphorylation of the kinase domain of TGFβRI, which in turn results in activation of the Smad pathway. This is therefore a targeted pathway for research into the application of peptide inhibitors in blocking the TGF-β-Smad signaling pathway. The aim of this study was to design a peptide inhibitor (homologous to the cytokine TGF-β) which, after binding to the TGFβRI/TGFβRII receptor, would block the cytokine binding and thus prevent the formation of an activating complex.

Methods

Preliminary work on the design and synthesis of inhibitors for TGFβRI/TGFβRII has allowed us to identify and describe five key regions of the TGF-β—TGFβRI/TGFβRII interface. The following five peptide inhibitors were synthesized for Region 1: 1.1 ALDAAYCFR, 1.2 LDAAYCFRN, 1.3 DAAYCFRNV, 1.4 AAYCFRNVQ, 1.5 AYCFRNVQD. The expression of the SEAP reporter gene, Smad2, Smad3, Smad4, and JNK1 gene was measured using quantitative real-time polymerase chain reaction.

Results

For Region 1 peptide inhibitors tested for TGFβRI/TGFβRII, reduced SEAP (reporter gene) expression was observed in cells of the MFB-F11 line, which suggests inhibited the formation of cytokine-receptor complexes.

Conclusions

For IP1_2, 1_3 and 1_5 Region 1 peptides tested for TGFβRI/TGFβRII, reduced cytokine-receptor signal by adding newly designed inhibitors. The study revealed an impact of these peptide inhibitors on the reduction of mRNA expression of Smad2, Smad3, Smad4 and JNK1 genes.

Abstract Image

评估与转化生长因子β细胞因子同源的多肽抑制剂阻断 TGFβRI/TGFβRII 受体复合体的有效性--试验研究
在纤维化过程中起关键作用的是转化生长因子β(TGF-β),它通过增加基质蛋白的转录来促进细胞外基质的生成。细胞因子 TGF-β 首先与 TGFβRII 受体(二聚体)结合,从而招募 TGFβRI 受体(二聚体)。由此形成的复合物导致 TGFβRI 的激酶结构域磷酸化,进而激活 Smad 通路。因此,这是研究多肽抑制剂在阻断 TGF-β-Smad 信号通路中应用的一个目标通路。本研究的目的是设计一种多肽抑制剂(与细胞因子 TGF-β 同源),它与 TGFβRI/TGFβRII 受体结合后,会阻断细胞因子的结合,从而阻止活化复合物的形成。
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来源期刊
Clinical and Translational Allergy
Clinical and Translational Allergy Immunology and Microbiology-Immunology
CiteScore
7.50
自引率
4.50%
发文量
117
审稿时长
12 weeks
期刊介绍: Clinical and Translational Allergy, one of several journals in the portfolio of the European Academy of Allergy and Clinical Immunology, provides a platform for the dissemination of allergy research and reviews, as well as EAACI position papers, task force reports and guidelines, amongst an international scientific audience. Clinical and Translational Allergy accepts clinical and translational research in the following areas and other related topics: asthma, rhinitis, rhinosinusitis, drug hypersensitivity, allergic conjunctivitis, allergic skin diseases, atopic eczema, urticaria, angioedema, venom hypersensitivity, anaphylaxis, food allergy, immunotherapy, immune modulators and biologics, animal models of allergic disease, immune mechanisms, or any other topic related to allergic disease.
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