Enzyme-Triggered Charge and Conformation Switching for Tumor-Selective Peptide-Drug Conjugates

  • J Med Chem. 2026 May 28;69(10):12417-12429. doi: 10.1021/acs.jmedchem.6c00326.
Jiaying Wei  1  2 ,  Qipeng Yan  1 ,  Xingyue Jiang  1 ,  Wei Xie  1 ,  Min Wei  1 ,  Yuan Dan  1 ,  Xia Wu  2  3 ,  Junfeng Shi  1  4
Affiliations
  • 1. Hunan Provincial Key Laboratory of Animal Models and Molecular Medicine, State Key Laboratory of Chemo/bio-Sensing and Chemometrics, School of Biomedical Science, Hunan University, Changsha, Hunan 410082, China.
  • 2. Department of Cardiology, The Central Hospital of Xiangtan (The Affiliated Hospital of Hunan University), Xiangtan, Xiangtan, Hunan 411100, China.
  • 3. Shenzhen International Institute for Biomedical Research, Shenzhen 518116, China.
  • 4. Shenzhen Research Institute Hunan University, Shenzhen, Guangdong 518000, China.
PMID: 42142047 DOI: 10.1021/acs.jmedchem.6c00326
Abstract

Functionalizing Anticancer drugs with activatable peptides offers a versatile strategy to achieve tumor-selective delivery while minimizing systemic toxicity. Here, we report a γ-glutamyltransferase (GGT)-responsive cell-penetrating peptide (P-EE) generated by γ-glutamyl masking of penetratin for tumor-selective activation in hepatocellular carcinoma. Upon GGT-mediated cleavage, P-EE restores its cationic charge and helical conformation, enabling efficient membrane translocation and selective accumulation in GGT-overexpressing tumor cells. P-EE showed enhanced internalization and approximately 5-fold higher cytotoxic potency in HepG2 cells compared with NHDF normal cells. Covalent conjugation of camptothecin (CPT) to P-EE yielded a peptide-drug conjugate (CPT-P-EE) with greatly improved aqueous solubility, potent antitumor activity, and over 50-fold reduced toxicity to normal cells. In vivo, CPT-P-EE significantly suppressed tumor growth and prolonged survival without inducing systemic toxicity. This study establishes a generalizable enzyme-activatable peptide-drug conjugate platform that integrates conformational switching with targeted delivery, offering a promising direction for precision chemotherapy against GGT-positive malignancies.

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