A small molecule PTER-selective inhibitor reduces food intake and body weight
PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic taurine metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remain unknown, limiting our ability to harness this pathway therapeutically. Here we solve crystal structures of a eukaryotic PTER in apo and product-bound forms. These structures uncover an unexpected pocket homology between PTER and histone deacetylase (HDAC) enzymes. We exploit this similarity to engineer a first-in-class substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs in vitro. Administration of PTERi to diet-induced obese mice reduces feeding, enhances GLP1-RA (glucagon like peptide 1 receptor agonist)-induced weight loss, and prevents weight regain after GLP1-RA discontinuation. The structure of PTER connects histone and metabolite deacetylation into a parallel conceptual framework and enables proof-of-concept data for pharmacological inhibition of PTER in obesity.
Authors
- Sipei Fu (ORCID: https://orcid.org/0000-0003-4967-2185)
- Xuchao Lyu
- Jan Spaas (ORCID: https://orcid.org/0000-0002-4953-2505)
- Stephen M. Hinshaw (ORCID: https://orcid.org/0000-0003-4215-5206)
- Jonathan Z. Long (ORCID: https://orcid.org/0000-0003-2631-7463)
- Daniel Fernández (ORCID: https://orcid.org/0000-0002-6221-152X)
- Shuliang Deng (ORCID: https://orcid.org/0000-0002-1543-2733)
- Robert E. Gerszten (ORCID: https://orcid.org/0000-0002-6767-7687)
- Shuke Xiao (ORCID: https://orcid.org/0000-0003-2103-128X)
- Lushun Wang (ORCID: https://orcid.org/0000-0002-8373-2199)
- Veronica Lynn Li
- April P. Carson (ORCID: https://orcid.org/0000-0002-7970-6756)
- Xu Shi
- Tinghu Zhang
- Usman Tahir
- Nathanael Gray
- Hlib Razumkov
- Bertha A Hidalgo
- Mark Benson
- Charleen Adams
- Wei Wei
- James G Wilson
- Jacob Barber
Institutions
- University of North Carolina at Chapel Hill (US)
- Beth Israel Deaconess Medical Center (US)
- Neurosciences Institute (US)
- University of Alabama at Birmingham (US)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-28
- DOI
- https://doi.org/10.64898/2026.01.26.701829
- Primary Topic
- Aldose Reductase and Taurine
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ono Pharma Foundation
- National Institutes of Health
- Wu Tsai Neurosciences Institute, Stanford University