Attaching two different fatty acids to a BimBH3 peptide created a cell-permeable, ultra-long-acting PTPN1/2 inhibitor with a >200 hour half-life that controlled blood sugar weekly in diabetic mice.
>200 hour half-lifeDual fatty acid-conjugated BimBH3 peptide in rats after subcutaneous injection, enabling once-weekly dosing
What the researchers found
By conjugating a long-chain fatty acid to the N-terminus and a medium-chain fatty acid to Lys2 of the BimBH3 peptide, the optimized analogue D6 achieved:
- Potent dual PTPN1/2 inhibition (IC50 = 107.6 nM for PTPN1, 3375 nM for PTPN2)
- 40-fold improved DPP-IV stability over the parent peptide
- Plasma half-life >200 hours in rats after subcutaneous injection
- Efficient cell permeability and uptake for intracellular target engagement
- Restored insulin signaling in HepG2 liver cells
- Once-weekly glycemic control in db/db diabetic mice
Why it matters
PTPN1 and PTPN2 are "undruggable" intracellular targets that negatively regulate insulin signaling. Small molecule inhibitors have failed due to selectivity issues. This dual fatty acid peptide approach solves the twin problems of cell entry and long duration, potentially creating a new class of insulin-sensitizing drugs for type 2 diabetes.
How the study worked
Researchers systematically explored dual fatty acid conjugation of BimBH3 peptides, testing different chain lengths and attachment positions. Lead compounds were evaluated for PTPN1/2 inhibition potency, DPP-IV resistance, cell permeability, pharmacokinetics in rats, and efficacy in db/db diabetic mice. Molecular docking studies characterized binding interactions with PTPN1/2 active sites.
What this study cannot tell us
Preclinical study in rats and mice only. The >200 hour half-life in rats may not translate directly to humans. PTPN2 inhibition raises immune safety concerns since PTPN2 regulates immune responses. The cell permeability mechanism and potential off-target effects need further characterization. Manufacturing scalability of dual-conjugated peptides was not addressed.
How to read the evidence
This is a medicinal chemistry and preclinical pharmacology study. The chemical design is innovative and well-validated, but all efficacy data is in diabetic mice. Human translation requires extensive further development.
When this study was published
Published in 2025 in the Journal of Medicinal Chemistry, this is a cutting-edge advance in peptide drug design.
The bigger picture
Fatty acid conjugation is the same strategy used in semaglutide and other long-acting peptide drugs, but those target extracellular receptors. This study extends the approach to intracellular targets, which is a significant advance. If peptides can be made to enter cells AND last for days, it greatly expands the druggable target space for peptide therapeutics.
Questions still open
- Could dual fatty acid conjugation be applied to other therapeutic peptides to make them cell-permeable and long-acting?
- What are the immune safety implications of inhibiting PTPN2, given its role in immune regulation?
- How does D6's insulin-sensitizing efficacy compare to existing diabetes drugs like metformin or GLP-1 agonists?
Common questions
What are PTPN1 and PTPN2?
Why is a >200 hour half-life significant for a peptide?
Read the original research
Dual Conjugation of Long- and Medium-Chain Fatty Acids to BimBH3 Peptide Yields Ultra Long-Acting Inhibitors of Intracellular PTPN1/2.
Journal of medicinal chemistry, 68(11), 11174-11187
Citation
Zhang, Chuanliang; Dong, Guozhen; Wu, Xiao; Chen, Jin; Wang, Yanqing; Gong, Liyan; Yang, Xianmin; Shi, Yiying; Gu, Zongwen; Gao, Xiang; Zheng, Yaning; Wu, Han; Zheng, Ke; Liu, Xiaochun; Gu, Yuchao. (2025). Dual Conjugation of Long- and Medium-Chain Fatty Acids to BimBH3 Peptide Yields Ultra Long-Acting Inhibitors of Intracellular PTPN1/2.. Journal of medicinal chemistry, 68(11), 11174-11187. https://doi.org/10.1021/acs.jmedchem.5c00147