Abstract
8-oxoGuanine DNA glycosylase 1 (OGG1) is the first known target of organocatalytic switches (ORCAs), rewriting the biochemical function of the enzyme, preferring AP sites over 8-oxoG. Previous reports have further indicated the possibility to use different chemotypes of organocatalytic switches to extend enzymatic control to pH at which OGG1 is commonly inactive. Compound pKa has been suggested to govern reaction turnover through the ability to abstract protons from the substrate, potentially expanding the descriptors necessary to monitor during classical structure-activity-relationship (SAR) studies. Here, we identify a minimal structure of organocatalytic switches - 4-Anilino pyridines and 6-Anilino pyrimidines are dimethyl-amino-pyridine (DMAP) type Brønsted-bases binding the active site of OGG1. Systematic interrogation of base properties through electron-donating (EDG) and electron-withdrawing (EWG) groups established that pKa at or slightly lower than the pH used is a proxy to predict com-pound activity. The lead structure was further identified as a potent scaffold from a screen in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis (MASH), where it significantly reduced hepatic fibrosis. These findings deepen the knowledge of the novel modulator class with implications for future enzyme targets and further probe development.
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