Iterative Optimization Yields Stapled Peptides with Superior Pharmacokinetics and Potency for Renal Fibrosis Treatment
Renal fibrosis, resulting from myofibroblast-mediated excessive extracellular matrix (ECM) deposition, lacks effective treatments. Novel peptide DR3penA developed by our group showed therapeutic potential for fibrotic diseases; however, its application was hindered by poor stability and bioavailability. To address this unmet need, we implemented stepwise optimization of DR3penA. The conformationally restricted analogs designed via structural predictions enhanced both activity and stability. Through structure-activity relationship analysis and cleavage site mapping, introducing unnatural amino acids improved stability. Fatty acid modifications conferred fibroblast-selective cytotoxicity and improved pharmacokinetics. After several rounds of progressive modification, peptide <b>27</b> exhibited remarkable stability, with a 5.68-fold extended half-life compared to DR3penA. Following profibrotic stimuli, peptide <b>27</b> effectively inhibited myofibroblast activation, epithelial-mesenchymal transition, and ECM synthesis. It also attenuated renal fibrosis in a unilateral ureteral obstruction model. Our study leverages multiple modifications that integrate cell and animal models to identify peptide <b>27</b> as a promising candidate for renal fibrosis therapy.
Authors
- Xiaokang Miao (ORCID: https://orcid.org/0000-0002-9124-6414)
- Junqiu Xie (ORCID: https://orcid.org/0000-0002-4808-7307)
- Bochuan Deng
- Cheng Lu (ORCID: https://orcid.org/0000-0002-7651-3924)
- Wenle Yang (ORCID: https://orcid.org/0009-0000-5504-5140)
- Liang Hong (ORCID: https://orcid.org/0000-0002-3489-0633)
- Tiantian Yan (ORCID: https://orcid.org/0000-0002-0811-9706)
- Guangjun Bao
- Ping Su (ORCID: https://orcid.org/0009-0003-4305-6549)
- Chenyu Wang (ORCID: https://orcid.org/0000-0003-1808-361X)
- Yue Yin (ORCID: https://orcid.org/0000-0002-7278-2246)
- Jiao Zhang (ORCID: https://orcid.org/0000-0001-5614-3420)
- Xiang Zhang (ORCID: https://orcid.org/0000-0003-1003-9892)
- Dan Wang (ORCID: https://orcid.org/0009-0000-9631-7050)
- Rui Wang (ORCID: https://orcid.org/0000-0002-4719-9921)
- Lei Shen (ORCID: https://orcid.org/0000-0002-3269-2254)
- Tingli Yu
Institutions
- North Sichuan Medical University (CN)
- Academy of Medical Sciences (GB)
- Shenzhen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking Union Medical College Hospital (CN)
- Institute of Physiology and Basic Medicine (RU)
- Xinjiang Institute of Materia Medica (CN)
- Drug Discovery Laboratory (Norway) (NO)
- Shenzhen University Health Science Center (CN)
- Lanzhou University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00133
- Citations
- 2
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 4.01