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

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

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.

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