Researchers Identify Novel Allosteric Inhibitors of Citrate Transporter NaCT for Metabolic and Neurological Disease
Scientists have discovered a new class of small molecule inhibitors targeting an allosteric binding site on NaCT (SLC13A5), a citrate transporter implicated in metabolic disease and a rare form of epilepsy. Unlike existing inhibitors that compete directly with the substrate, these compounds act at the dimer interface — a previously unexplored site. The findings open a new avenue for developing treatments for SLC13A5 Epilepsy and related metabolic conditions.
Researchers conducted a virtual screen of 3.5 million compounds from the ZINC20 database against a putative allosteric site at the dimer interface of NaCT, a sodium-dependent citrate transporter encoded by SLC13A5. From 54 candidates tested in a cell-based citrate uptake assay, three initial weak inhibitors were identified, and evaluation of 26 structurally related analogs yielded six compounds with improved potency, with the best showing IC50 values of approximately 12.78 µM and 15.49 µM. The team further characterized the binding site by integrating structural data, deep mutational scanning, and comparisons with homologous transporter structures, highlighting residues such as Phe362 as important for ligand modulation. NaCT regulates citrate homeostasis and has been linked to both metabolic disorders and SLC13A5 Epilepsy, a rare pediatric disease characterized by severe seizures and neurodevelopmental delays. Current inhibitors are substrate-mimicking molecules that occupy the primary binding site, so this allosteric series represents a chemically distinct approach that could offer improved selectivity or complementary therapeutic profiles. The study establishes a structural and chemical foundation for rational drug design targeting this newly identified pocket.
What's missing
The study reports IC50 values in the low micromolar range (12–15 µM), which are modest potencies for drug candidates; the authors do not discuss selectivity of these compounds against related SLC13 family transporters or off-target liabilities. In vivo efficacy, pharmacokinetic properties, and toxicity data are absent, as expected at this early stage. The mechanism by which allosteric inhibition at the dimer interface translates to reduced citrate transport activity is not yet fully elucidated. As a preprint, these findings have not yet undergone formal peer review.
What different sources said
- bioRxivCenter
Targeting an allosteric binding site in the citrate transporter NaCT (SLC13A5)
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