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

作     者：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 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

作者机构：Institute of Materia Medica and Research Unit of Peptide ScienceChinese Academy of Medical SciencesPeking Union Medical CollegeBeijing 100050China Key Laboratory of Preclinical Study for New Drugs of Gansu ProvinceSchool of Basic Medical SciencesLanzhou UniversityLanzhou 730000China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第2期

页      面：722-738页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 10[医学] 

基　　金：supported by the CAMS Innovation Fund for Medical Sciences(CIFMS,Nos.2019-I2M-5-074,2021-I2M-1-026,2021-I2M-3-001,2022-I2M-2-002,China) the Program for the Ministry of Education“Peptide Drugs”Innovation Team(No.IRT_15R27,China) the Fundamental Research Funds for the Central Universities(No.lzujbky-2021-it17,China)。 

主　　题：Peptide Structure modification Pulmonary fibrosis miR-23b-5p AQP5 

摘      要：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_(2))could be modified to improve stability and antifibrotic activity,and the unnatural hydrophobic amino acids a-(4-pentenyl)-Ala and D-Ala were considered in this study.DR3penA(DHa-(4-pentenyl)-ANPQIR-NH_(2))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.