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A small molecule PTER-selective inhibitor reduces food intake and body weight
Open accessPreprint — published as 10.1016/j.chembiol.2026.02.005 · Paper page
Abstract
Summary: 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.
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Metadata
- Authors
- Fu, S., Wang, L., Li, V. L., Lyu, X., Wei, W., Shi, X., Deng, S., Barber, J. L., Tahir, U. A., Adams, C., Carson, A., Hidalgo, B., Raffield, L. M., Wilson, J. G., Razumkov, H., Xiao, S., Spaas, J., Fernandez, D., Zhang, T., Gerszten, R. E., Benson, M. D., Gray, N. S., Hinshaw, S. M., & Long, J. Z.
- Affiliations
- Stanford Medicine (US)
- Stanford University (US)
- Beth Israel Deaconess Medical Center (US)
- University of Alabama at Birmingham (US)
- University of North Carolina at Chapel Hill (US)
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA
- Corresponding author
- Long, Jonathan Z.
- ORCID
- Venue
- Cell chemical biology
- Publisher
- openRxiv
- Published
- 2026-01-28
- Volume
- 33
- Issue
- 3
- Pages
- 353-363.e7
- ISSN
- 2451-9448 (ISSN-L)
- PMC
- PMC12873775
- OpenAlex
- W7134286800
- Cited by
- 2
- References
- 44
- Citations by year
- 2026: 2
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by-nc)
- PubMed Central (submittedVersion)
- Funders
- Ono Pharma Foundation
- National Institutes of Health (1r01dk137983-01a1)
- Wu Tsai Neurosciences Institute, Stanford University
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124265, R01DK136526)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- amidohydrolase, small molecule inhibitors, substrate-competitive inhibition, crystal structure, obesity, dietary intake, body weight, GLP-1 receptor agonists, weight regain, diet-induced obesity, enzyme selectivity
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