A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis
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 unnatura...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383522003896 |
| _version_ | 1797897332368343040 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dan Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T07:55:50Z |
| format | Article |
| id | doaj.art-e184d3ecb8c64f30812309f4c613eb50 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-10T07:55:50Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-e184d3ecb8c64f30812309f4c613eb502023-02-23T04:31:15ZengElsevierActa Pharmaceutica Sinica B2211-38352023-02-01132722738A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axisDan Wang0Bochuan Deng1Lu Cheng2Jieru Li3Jiao Zhang4Xiang Zhang5Xiaomin Guo6Tiantian Yan7Xin Yue8Yingying An9Bangzhi Zhang10Wenle Yang11Junqiu Xie12Rui Wang13Institute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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, ChinaInstitute 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; Corresponding authors. Tel.: +86 931 8915522; fax: +86 931 8911255.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; Corresponding authors. Tel.: +86 931 8915522; fax: +86 931 8911255.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.http://www.sciencedirect.com/science/article/pii/S2211383522003896PeptideStructure modificationPulmonary fibrosismiR-23b-5pAQP5 |
| spellingShingle | 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 A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis Acta Pharmaceutica Sinica B Peptide Structure modification Pulmonary fibrosis miR-23b-5p AQP5 |
| title | A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis |
| title_full | A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis |
| title_fullStr | A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis |
| title_full_unstemmed | A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis |
| title_short | A novel and low-toxic peptide DR3penA alleviates pulmonary fibrosis by regulating the MAPK/miR-23b-5p/AQP5 signaling axis |
| title_sort | novel and low toxic peptide dr3pena alleviates pulmonary fibrosis by regulating the mapk mir 23b 5p aqp5 signaling axis |
| topic | Peptide Structure modification Pulmonary fibrosis miR-23b-5p AQP5 |
| url | http://www.sciencedirect.com/science/article/pii/S2211383522003896 |
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