2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel and highly potent peptides targeting syntenin

Design, synthesis, and biological evaluation of novel and highly potent peptides targeting syntenin

  • Eur J Med Chem. 2025 May 5:289:117446. doi: 10.1016/j.ejmech.2025.117446.
Yang Zhou 1,  Yuting Wang 2,  Juanjuan Liu 3,  Yu Bai 4,  Jinliang Ma 5,  Miao-Miao Niu 2,  Jindong Li 6,  Haijing Jiang 7
Affiliations

Affiliations

  • 1 Department of Pathology, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213100, China. Electronic address: yangzhpathology@163.com.
  • 2 Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 Department of Pharmacy, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, China.
  • 4 Department of Urology, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213100, China; Department of Urology, Traditional Chinese Medicine Hospital of Gonghe County, Gonghe County, Hainan Prefecture, 813099, China.
  • 5 Department of Urology, Traditional Chinese Medicine Hospital of Gonghe County, Gonghe County, Hainan Prefecture, 813099, China.
  • 6 Department of Pharmacy, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, China. Electronic address: lijindong20230419@njmu.edu.cn.
  • 7 Drug Clinical Trial Facility Office, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China. Electronic address: jshajhj8@163.com.
PMID: 40020425 DOI: 10.1016/j.ejmech.2025.117446
Abstract

Syntenin, an intracellular scaffold protein, plays a critical role in renal cell carcinoma (RCC) progression, underscoring its potential as a therapeutic target. Herein, we report a novel, highly efficient, and stable peptide inhibitor (PDPP-3) that exhibits excellent inhibitory effects on syntenin. We have constructed a combined virtual screening scheme based on pharmacophore modeling and molecular docking to identify six potential d-amino acid-containing peptide inhibitors targeting syntenin. Among them, PDPP-3 showed the best inhibitory activity against syntenin. Binding affinity experiments and biostability experiments indicated that the interaction between PDPP-3 and syntenin displayed nanomolar-level binding affinity (Kd = 6.15 ± 0.12 nM) and superior biostability in serum. Molecular dynamics simulation results further confirmed that PDPP-3 could stably bind to the active site of syntenin. Additionally, cytotoxicity test results showed that PDPP-3 exhibited potent inhibitory effects on various types of renal Cancer cells, with the best inhibitory effect on SK-RC-20 cells. More importantly, PDPP-3 significantly downregulates the expression of matrix metalloenzymes MT1-MMP and MMP2, which are pivotal for tumor invasion, and demonstrates inhibitory effects on tumor growth in SK-RC-20 derived xenografts. These data suggest that PDPP-3 may be a very promising candidate drug for the treatment of RCC.

Keywords

Molecular dynamics; Peptide inhibitor; Renal cell carcinoma (RCC); Syntenin; Virtual screening.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P10331
    Syntenin Peptide Inhibitor