2. Academic Validation
  3. Iterative Optimization Yields Stapled Peptides with Superior Pharmacokinetics and Potency for Renal Fibrosis Treatment

Iterative Optimization Yields Stapled Peptides with Superior Pharmacokinetics and Potency for Renal Fibrosis Treatment

  • J Med Chem. 2025 Apr 24;68(8):8516-8529. doi: 10.1021/acs.jmedchem.5c00133.
Bochuan Deng 1,  Ping Su 1,  Lu Cheng 2,  Jiao Zhang 1,  Xiang Zhang 1,  Tingli Yu 1,  Guangjun Bao 1,  Tiantian Yan 1,  Yue Yin 1,  Lei Shen 1,  Dan Wang 3,  Liang Hong 4,  Xiaokang Miao 1,  Wenle Yang 1,  Chenyu Wang 1,  Junqiu Xie 1,  Rui Wang 1 5
Affiliations

Affiliations

  • 1 Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China.
  • 2 School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518060, China.
  • 3 Institute of Basic Medicine, North Sichuan Medical College, Nanchong 637000, China.
  • 4 Guangdong Provincial Key Laboratory of Chiral Molecular and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 5 Institute of Materia Medica and Research Unit of Peptide Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
PMID: 40199779 DOI: 10.1021/acs.jmedchem.5c00133
Abstract

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 27 exhibited remarkable stability, with a 5.68-fold extended half-life compared to DR3penA. Following profibrotic stimuli, peptide 27 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 27 as a promising candidate for renal fibrosis therapy.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z