Novel Quinic Acid Glycerates from Tussilago farfara Inhibit Polypeptide GalNAc‐Transferase

Abstract The discovery of a bioactive inhibitor tool for human polypeptide N ‐acetylgalactosaminyl transferases (GalNAc‐Ts), the initiating enzyme for mucin‐type O ‐glycosylation, remains challenging. In the present study, we identified an array of quinic acid derivatives, including four new glycerates ( 1 – 4 ) from Tussilago farfara , a traditional Chinese medicinal plant, as active inhibitors of GalNAc‐T2 using a combined screening approach with a cell‐based T2‐specific sensor and purified enzyme assay. These inhibitors dose‐dependently inhibited human GalNAc‐T2 but did not affect O ‐linked N ‐acetylglucosamine transferase (OGT), the other type of glycosyltransferase. Importantly, they are not cytotoxic and retain inhibitory activity in cells lacking elongated O ‐glycans, which are eliminated by the CRISPR/Cas9 gene editing tool. A structure‐activity relationship study unveiled a novel quinic acid‐caffeic acid conjugate pharmacophore that directs inhibition. Overall, these new natural product inhibitors could serve as a basis for developing an inhibitor tool for GalNAc‐T2.