Dual Conjugation of Long- and Medium-Chain Fatty Acids to BimBH3 Peptide Yields Ultra Long-Acting Inhibitors of Intracellular PTPN1/2

  • J Med Chem. 2025 Jun 12;68(11):11174-11187. doi: 10.1021/acs.jmedchem.5c00147.
Chuanliang Zhang  1  2 ,  Guozhen Dong  1 ,  Xiao Wu  3 ,  Jin Chen  4 ,  Yanqing Wang  4 ,  Liyan Gong  1 ,  Xianmin Yang  1 ,  Yiying Shi  1 ,  Zongwen Gu  1 ,  Xiang Gao  1 ,  Yaning Zheng  4 ,  Han Wu  4 ,  Ke Zheng  1 ,  Xiaochun Liu  2 ,  Yuchao Gu  4  2
Affiliations
  • 1. Qingdao Key Laboratory of Biomacromolecular Drug Discovery and Development, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
  • 2. School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 3. Pulmonary and Critical Care Medicine Department,vQingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao 266000, China.
  • 4. Qingdao Center of Technology Innovation for Shark Antibody Development, College of Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
PMID: 40458949 DOI: 10.1021/acs.jmedchem.5c00147
Abstract

Fatty acid derivatization is a promising strategy for discovering long-acting peptide therapeutics, but intracellular targeting remains challenging due to insufficient membrane permeability. Here, we report a dual fatty acid conjugation approach to develop ultralong-acting inhibitors of intracellular PTPN1/2. By conjugating a long-chain fatty acid/diacid to the N-terminus and a medium-chain fatty acid/diacid to Lys2 of BimBH3 peptide, we achieved efficient cell permeability and uptake for intracellular target inhibition and metabolic stability for long-acting in vivo efficacy. The optimized analogue D6 exhibited potent dual PTPN1/2 inhibition (IC50 = 107.6 nM and 3375 nM), 40-fold improved DPP-IV stability, and prolonged plasma half-life (>200 h) in rats following sc administration. D6 exhibited efficient cell permeability, restored Insulin signaling in HepG2 cells and demonstrated once-weekly glycemic control in db/db mice. Molecular docking revealed key interactions with PTPN1/2 active sites. This work demonstrates a strategy for designing cell-permeable, long-acting peptide inhibitors of intracellular targets.

Products