Small Molecule Inhibition of Sulfotransferases
Human cystolic sulfotransferases (SULTs) were at one time believed to serve solely in their role in detoxification of the metabolome through sulfonation of various substrates, promoting renal clearance. Later, it was learned that these enzymes also play a significant role in Parkinson’s disease, cancer, hemophilia, chronic inflammation, viral entry into cell, and neurodegeneration, while contributing to other disease-relevant processes. SULT inhibitors, which have not been explored as a therapeutic option, could generate novel drug leads and provide important insight into the balance the enzymes play between maintaining homeostasis and disease progression.
Description
A new allosteric site on SULT1A3 has been identified and targeted by the first newly-developed synthetic allosteric inhibitors. Researchers have also developed a combined NMR-based experimental and computational method that can accurately predict this site’s response to inhibitor binding which can be used to aid in designing other compounds. Inhibiting of SULTs with small molecule drugs may be a successful and less risky alternative to MAO inhibitors, widely used in treating diseases like Parkinson’s, that come with the potential for life-threatening side effects.Applications
· Generating novel drug candidates· Controlling neurotransmitter levels
· Treating Parkinson’s disease, hemophilia, cancer, chronic inflammation, viral infection, and neurodegeneration
· Predicting response to new inhibitors
· A stable human mammary epithelial cell line overexpresses SULT1A3 to facilitate the evaluation of the potency of compounds in cells
Advantages
· As-yet unexplored option for treating a number of diseases· May be less dangerous than current treatment options
· Yields insight into the role enzymes play in maintaining homeostasis and disease progression