Discovery and Characterization of a Selective Inhibitor of Synaptojanin1 5-Phosphatase Activity

Sep 19, 2025ACS pharmacology & translational science

Identification and Study of a Compound That Selectively Blocks Synaptojanin1 Enzyme Activity

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Abstract

Gambogic acid is identified as a potent noncompetitive inhibitor of Synaptojanin1 with an IC50 value of 0.51 μM.

Epigallocatechin monogallate inhibits all tested human 5-phosphatases, indicating broad activity.
Gambogic acid selectively inhibits Synaptojanin1, distinguishing it from other 5-phosphatases.
Kinetic analysis suggests gambogic acid targets a less conserved allosteric pocket rather than the active site.
Inhibition of Synaptojanin1's 5-phosphatase activity may have therapeutic implications for diseases like Alzheimer's and epilepsy.

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Synaptojanin1 is a presynaptic phosphoinositide phosphatase that harbors two catalytic domains: an N-terminal suppressor of actin 1-like (Sac1) domain that predominantly dephosphorylates PI(3)P and PI(4)-P and a central 5-phosphatase (5-PPase) domain that dephosphorylates PI-(4,5)-Pand PI-(3,4,5)-P. While loss-of-function mutations in Synaptojanin1 are associated with epilepsy and Parkinson's disease, inhibition of the 5-phosphatase activity of Synaptojanin1 was identified as a potential therapeutic approach for Alzheimer's disease, Down syndrome, and TBC1D24-associated epilepsy. However, the high conservation of active site residues among the different human 5-phosphatases has hampered the identification of Synaptojanin1-selective inhibitors. Here, we identified epigallocatechin monogallate and gambogic acid as inhibitors of the Synaptojanin1 5-phosphatase activity via a combination of high-throughput screening and structure-based virtual screening. While epigallocatechin monogallate shows promiscuous inhibition of all tested human 5-phosphatase, gambogic acid is selective for Synatojanin1. Correspondingly, kinetic analysis demonstrates that gambogic acid acts as a potent (= 0.51 μM) noncompetitive Synaptojanin1 inhibitor, suggesting that it targets a less conserved allosteric pocket rather than the active site. Together, these findings propose gambogic acid as a promising lead compound for the development of new selective inhibitors of Synaptojanin1. 2 3i K

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Discovery and Characterization of a Selective Inhibitor of Synaptojanin1 5-Phosphatase Activity

Abstract

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