A small molecule PTER-selective inhibitor reduces food intake and body weight

Cell chemical biology
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Sipei Fu, Lushun Wang, Veronica L Li, Xuchao Lyu, Wei Wei, Xu Shi, Shuliang Deng, Jacob L Barber, Usman A Tahir, Charleen Adams, April Carson, Bertha Hidalgo, Laura M Raffield, James G Wilson, Hlib Razumkov, Shuke Xiao, Jan Spaas, Daniel Fernandez, Tinghu Zhang, Robert E Gerszten, Mark D Benson, Nathanael S Gray, Stephen M Hinshaw, Jonathan Z Long

Cell Chem Biol. 2026 Mar 9:S2451-9456(26)00060-7. doi: 10.1016/j.chembiol.2026.02.005. Online ahead of print.

ABSTRACT

PTER (phosphotriesterase-related) is an amidohydrolase that mediates catabolism of the anorexigenic metabolite N-acetyltaurine. However, the structural basis of PTER ligand binding and catalysis remains 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 substrate-competitive PTER inhibitor called PTERi with nanomolar potency and >100-fold selectivity for PTER over HDACs in vitro. The administration of PTERi to diet-induced obese mice reduces feeding, enhances glucagon-like peptide 1 receptor agonist (GLP1-RA)-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 the pharmacological inhibition of PTER in obesity.

PMID:41806828 | PMC:PMC12981338 | DOI:10.1016/j.chembiol.2026.02.005