Wang Dan, Deng Bochuan, Cheng Lu, Li Jieru, Zhang Jiao, Zhang Xiang, Guo Xiaomin, Yan Tiantian, Yue Xin, An Yingying, Zhang Bangzhi, Yang Wenle, Xie Junqiu, Wang Rui
Institute of Materia Medica and Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
Acta Pharm Sin B. 2023 Feb;13(2):722-738. doi: 10.1016/j.apsb.2022.09.001. Epub 2022 Sep 5.
Pulmonary fibrosis (PF) is a pathological change caused by repeated injuries and repair dysfunction of the alveolar epithelium. Our previous study revealed that the residues Asn3 and Asn4 of peptide DR8 (DHNNPQIR-NH) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids -(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DH-(4-pentenyl)-ANPQIR-NH) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis and . Moreover, DR3penA has a dosage advantage over pirfenidone through the conversion of drug bioavailability under different routes of administration. A mechanistic study revealed that DR3penA increased the expression of aquaporin 5 (AQP5) by inhibiting the upregulation of miR-23b-5p and the mitogen-activated protein kinase (MAPK) pathway, indicating that DR3penA may alleviate PF by regulating MAPK/miR-23b-5p/AQP5. Safety evaluation showed that DR3penA is a peptide drug without obvious toxicity or acute side effects and has significantly improved safety compared to DR8. Thus, our findings suggest that DR3penA, as a novel and low-toxic peptide, has the potential to be a leading compound for PF therapy, which provides a foundation for the development of peptide drugs for fibrosis-related diseases.
肺纤维化（PF）是由肺泡上皮反复损伤和修复功能障碍引起的病理变化。我们之前的研究表明，肽DR8（DHNNPQIR-NH）的Asn3和Asn4残基可以被修饰以提高稳定性和抗纤维化活性，本研究考虑了非天然疏水氨基酸-(4-戊烯基)-Ala和d-Ala。DR3penA（DH-(4-戊烯基)-ANPQIR-NH）在血清中具有更长的半衰期，并且能显著抑制氧化损伤、上皮-间质转化（EMT）和成纤维作用。此外，通过不同给药途径下药物生物利用度的转化，DR3penA比吡非尼酮具有剂量优势。一项机制研究表明，DR3penA通过抑制miR-23b-5p的上调和丝裂原活化蛋白激酶（MAPK）途径来增加水通道蛋白5（AQP5）的表达，表明DR3penA可能通过调节MAPK/miR-23b-5p/AQP5来减轻PF。安全性评估表明，DR3penA是一种无明显毒性或急性副作用的肽类药物，与DR8相比安全性有显著提高。因此，我们的研究结果表明，DR3penA作为一种新型低毒肽，有潜力成为PF治疗的先导化合物，为纤维化相关疾病的肽类药物开发提供了基础。
