The human cytosolic sulfotransferases (SULTs) are a class of thirteen metabolic enzymes that utilize an adenosine-based co-factor, 3’-phosphoadenosine-5’-phosphosulfate (PAPS), for sulfuryl group (SO<sub>3</sub><sup>–</sup>) transfer to drugs, xenobiotics, hormones, and neurotransmitters. SULT activity has been linked to numerous diseases including depression, obesity, neurodegeneration, skin diseases, and cancer. Isoform-specific inhibition of SULTs is challenging due to the high degree of structural homology of the enzyme class, particularly of their active sites. Allosteric regulation, until now, has remained a largely unexplored area of SULT biology. We have developed the first synthetic, isoform specific allosteric inhibitors of SULT1A3, an isoform responsible for the metabolism of neurotransmitters, such as serotonin and dopamine. Inhibitor specificities and affinities were validated through enzymatic assays with other cytosolic SULT isoforms. Efficacies of lead compounds were confirmed in mammalian cells and are currently being investigated in animals. Additional work is focused toward developing allosteric inhibitors of additional SULT isoforms to demonstrate SULT inhibition as a platform technology for novel small molecule therapeutics.

Small molecule allosteric inhibition of cytosolic sulfotransferases

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ACS Fall 2022

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