JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Zihan Shi,Xianyan Liu,Shuohan Wu,Nazi Song,Qinglin Tang,Haonan Li,Suijia Luo,Albert S. C. Chan,Xiaoqing Cai,Han Liu,Xianxing Jiang
Liver fibrosis is a condition characterized by aberrant proliferation of connective tissue in the liver resulting from diverse etiological factors. G protein-coupled receptor GPR55 has recently been identified as a regulator of liver diseases. Herein, we report the discovery of a cyclic peptide P1-1 that antagonizes GPR55 and suppresses collagen secretion in hepatic stellate cells. The alanine scanning and docking study was carried out to predict the binding mode and allowed for further structural optimization of peptide antagonists for GPR55. The subsequent in vivo study demonstrated that P1-1 ameliorates CCl4-induce and MCD-diet-induce acute liver inflammation and fibrosis. Further study indicates that P1-1 reduces reactive oxygen species (ROS) production, attenuates ER stress, and inhibits mitochondria-associated hepatocyte apoptosis. In this work, we provided the first successful example of antagonizing GPR55 for liver inflammation and fibrosis, which validates GPR55 as a promising target for the treatment of liver fibrosis and affords a high-potent GPR55 antagonist P1-1 as a potential therapeutic candidate.
研究领域:
药理学
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分子生物学
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DOI
PubMed
高影响因子
LANGMUIR
·
2025
·
IF 3.9
Yaohui Du,Chuanmei Tang,Bowen Li,Lei Yue,Rongxin Su,Wei Qi,Xianbao Cui,Yuefei Wang
The study explored the impact of peptide conformations on the efficiency of nucleic acids transfection by designing two sets of linear (liKK and liRR) and cyclic peptides (cyKK and cyRR) with various sequences (KK: KKKKCRGDSCKKKK and RR: RRRRCLLLLCRRRR). Incorporating peptides in the liposome formulation improved gene transfection efficiency compared to the peptide and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) alone. The results revealed that adding linear peptides demonstrated a higher delivery efficiency in comparison to cyclic peptides in transfection formulations. Additionally, two effective groups of transfection formulations were established. The liKK/DOTAP/DOPE formulation proved exceptional at delivering mRNA, achieving a transfection efficiency of 93.3%, comparable to that of Lipofectamine 2000 (91.7%). In contrast, the liRR/DOTAP/DOPE formulation effectively delivered both pDNA and siRNA. The pDNA transfection efficiency reached 42.3%, closely matching Lipofectamine 2000 (43.9%), while the siRNA transfection efficiency hit 90.7%, surpassing Lipofectamine 2000’s performance (85.4%). The transfection efficiency of linear conformational formulations is superior to that of cyclic ones. Our research provides new options for liposome formulations and offers valuable insights for designing peptide-based gene delivery vectors with different conformations.
研究领域:
生物化学
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分子生物学
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药物递送系统
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Nazi Song,Haonan Li,Qinglin Tang,Suijia Luo,Zihan Shi,Qian Zhao,Runkai Li,Yili Chen,Xiaoqing Cai,Xianxing Jiang
Liver fibrosis is the undesirable result of excessive deposition of the extracellular matrix (ECM), and elastin is known as one of the key ECM components. Under specific pathological conditions, elastin undergoes degradation to produce elastin-derived peptides (EDPs), which bind to elastin-binding protein (EBP) to activate corresponding signal pathways, thus accelerating fibrosis progression. Herein, we describe the discovery of novel cyclic peptides that function as potent and stable inhibitors to interfere with the peptide–protein interaction between EDPs and EBP. Remarkably, CXJ-2 exhibited potent activities to inhibit the PI3K/ERK pathway and decrease hepatic stellate cell proliferation and migration. The subsequent in vivo study demonstrated that CXJ-2 possessed potent antifibrotic efficacy in ameliorating CCl4-induced liver fibrosis. This work provides a successful pharmacological strategy for the development of novel inhibitors of EDPs–EBP interaction, which sheds new light on how cyclic peptides disrupt peptide–protein interaction and may also provide new structure-oriented therapeutic candidates in liver fibrosis.
研究领域:
药理学
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生物化学
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DOI
PubMed
高影响因子
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY
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2020
·Vol. 84
·期 6
·1153-1159
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IF 1.516
Xue Guangpu,Xie Xie,Zhou Yang,Yuan Cai,Huang Mingdong,Jiang Longguang
Peptidic inhibitors of proteases are attracting increasing interest not only as drug candidates but also for studying the function and regulation mechanisms of these enzymes. Previously, we screened out a cyclic peptide inhibitor of human uPA and found that Ala substitution of P2 residue turns upain-1 to a substrate. To further investigate the effect of P2 residue on the peptide behavior transformation, we constructed upain-1-W3F, which has Phe replacement in the P2 position. We determined KD and Ki of upain-1-W3F and found that upain-1-W3F might still exist as an inhibitor. Furthermore, the high-resolution crystal structure of upain-1-W3F·uPA reveals that upain-1-W3F indeed stays as an intact inhibitor bind to uPA. We thus propose that the P2 residue plays a nonnegligible role in the conversion of upain-1 to a substrate. These results also proposed a strategy to optimize the pharmacological properties of peptide-based drug candidates by hydrophobicity and steric hindrance.Abbreviations : uPA: urokinase-type plasminogen activator; SPD: serine protease domain; S1 pocket: specific substrate-binding pocket
研究领域:
药理学
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生物化学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
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IF 5.714
Min Luo,Dan Luo,Jie Liu,Huailing Wang,Xiaoyu Liu,Min Yang,Fangfang Tian,Suofu Qin,Yuying Li
Probiotics are living bacteria that provide health benefits to the host when consumed in sufficient quantities. However, the protective effect of the bioactive peptides isolated from the probiotics against benzo(α)pyrene (BaP) induced gastrointestinal injury has never been investigated. The current work used a bio-assay guided technique to identify-four new cyclic peptides in BaP-induced Caco-2 cell culture and mouse colitis model. Lactobacillus rhamnosus cycle (Thr-His-Ala-Trp) peptide-1 (LRCP-1) effectively inhibited BaP-induced epithelial cytokine over-release and intracellular ROS over-production. Simultaneously, LRCP-1 attenuated BaP-induced NAD (P)H: oxidases (NOXs), Matrix metalloproteinases (MMPs) over-expression, respectively. Furthermore, increased NAD (P)H: quinone oxidoreductase 1 (NQO1)/heme oxygenase-1 (HO-1)/nuclear factor E2-related factor 2 (Nrf2) expression and aryl hydrocarbon receptor (AhR) pathway activation induced by the BaP-exposure were also inhibited after the LRCP-1 treatment. Notably, LRCP-1 is a promising agent protecting gastrointestinal epithelial cells from BaP-induced inflammatory and oxidative damages.
研究领域:
胃肠病学
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免疫学
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分子生物学
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毒理学
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PubMed
高影响因子
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