期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 382, 期 2, 页码 100-112出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.121.001031
关键词
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资金
- CAMS Innovation Fund for Medical Sciences (CIFMS) [2019-I2M-5-074, 2021-I2M-1-026, 2021-I2M-3-001]
- Program for the Ministry of Education Peptide Drugs Innovation Team [IRT 15R27]
- Gansu Science and Technology Program [18JR2RA031]
- Lanzhou Science and Technology Bureau [2019-4-4]
- Fundamental Research Funds for the Central Universities [lzujbky-2021-it17]
Pulmonary fibrosis (PF) is an interstitial lung disease with a poor prognosis and lacks an ideal clinical treatment strategy. Researchers have discovered that the antioxidant peptide DR8, extracted and purified from rapeseed, can alleviate PF. They have synthesized a DR8 analog called DR7dA, which demonstrated superior anti-fibrotic activity compared to DR8. Additionally, DR7dA attenuated PF by inhibiting extracellular matrix deposition and oxidative stress through the blockade of the MAPK pathway.
Pulmonary fibrosis (PF), which is characterized by enhanced extracellular matrix (ECM) deposition, is an interstitial lung disease that lacks an ideal clinical treatment strategy. It has an extremely poor prognosis, with an average survival of 3-5 years after diagnosis. Our previous studies have shown that the antioxidant peptide DR8 (DHNNPQIR-NH2), which is extracted and purified from rapeseed, can alleviate PF and renal fibrosis. However, natural peptides are easily degraded by proteases in vivo, which limits their potency. We have since synthesized a series of DR 8 analogs based on amino acid scanning substitution. DR7dA [DHNNPQ (D-alanine) R-NH2] is an analog of DR8 in which L-isoleucine (L-Ile) is replaced with D-alanine (D-Ala), and its half-life is better than that of DR8. In the current study, we verified that DR7dA ameliorated tumor growth factor (TGF)-beta 1-induced fibrogenesis and bleomycin-induced PF. The results indicated that DR7dA reduced the protein and mRNA levels of TGF-beta 1 target genes in TGF-beta 1-induced models. Surprisingly, DR7dA blocked fibrosis in a lower concentration range than DR8 in cells. In addition, DR7dA ameliorated tissue pathologic changes and ECM accumulation in mice. BLM caused severe oxidative damage, but administration of DR7dA reduced oxidative stress and restored antioxidant defense. Mechanistic studies suggested that DR7dA inhibits ERK, P38, and JNK phosphorylation in vivo and in vitro. All results indicated that DR7dA attenuated PF by inhibiting ECM deposition and oxidative stress via blockade of the mitogen-activated protein kinase (MAPK) pathway. Hence, compared with its parent peptide, DR7dA has higher druggability and could be a candidate compound for PF treatment in the future. SIGNIFICANCE STATEMENT In order to improve druggability of DR8, we investigated the structure-activity relationship of it and replaced the L-isoleucine with D-alanine. We found that the stability and antifibrotic activity of DR7dA were significantly improved than DR8, as well as DR7dA significantly attenuated tumor growth factor (TGF)beta 1-induced fibrogenesis and ameliorated bleomycin-induced fibrosis by inhibiting extracellular matrix deposition and oxidative stress via blockade of the MAPK pathway, suggesting DR7dA may be a promising candidate compound for the treatment of PF.
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