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

  • Acta Pharm Sin B. 2023 Feb;13(2):722-738. doi: 10.1016/j.apsb.2022.09.001.
Dan Wang  1  2 ,  Bochuan Deng  1  2 ,  Lu Cheng  1  2 ,  Jieru Li  1  2 ,  Jiao Zhang  1  2 ,  Xiang Zhang  1  2 ,  Xiaomin Guo  1  2 ,  Tiantian Yan  1  2 ,  Xin Yue  1  2 ,  Yingying An  1  2 ,  Bangzhi Zhang  1  2 ,  Wenle Yang  1  2 ,  Junqiu Xie  1  2 ,  Rui Wang  1  2
Affiliations
  • 1. Institute of Materia Medica and Research Unit of Peptide Science, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
  • 2. Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China.
PMID: 36873181 DOI: 10.1016/j.apsb.2022.09.001
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.

Keywords
AQP5; Peptide; Pulmonary fibrosis; Structure modification; miR-23b-5p.
Products