A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis.

Dan Wang; Bochuan Deng; Lu Cheng; Jieru LI; Jiao Zhang; Xiang Zhang; Xiaomin Guo; Tiantian Yan; Xin Yue; Yingying AN; Bangzhi Zhang; Wenle Yang; Junqiu Xie; Rui Wang

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A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis.

Author: Dan WANG ¹ ; Bochuan DENG ¹ ; Lu CHENG ¹ ; Jieru LI ¹ ; Jiao ZHANG ¹ ; Xiang ZHANG ¹ ; Xiaomin GUO ¹ ; Tiantian YAN ¹ ; Xin YUE ¹ ; Yingying AN ¹ ; Bangzhi ZHANG ¹ ; Wenle YANG ¹ ; Junqiu XIE ¹ ; Rui WANG ¹
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1. Institute of Materia Medica and Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
Publication Type:Journal Article
Keywords: AQP5; Peptide; Pulmonary fibrosis; Structure modification; miR-23b-5p
From: Acta Pharmaceutica Sinica B 2023;13(2):722-738
CountryChina
Language:English
Abstract: 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-NH₂) could be modified to improve stability and antifibrotic activity, and the unnatural hydrophobic amino acids α-(4-pentenyl)-Ala and d-Ala were considered in this study. DR3penA (DHα-(4-pentenyl)-ANPQIR-NH₂) was verified to have a longer half-life in serum and to significantly inhibit oxidative damage, epithelial-mesenchymal transition (EMT) and fibrogenesis in vitro and in vivo. 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.