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

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. A novel class of quinic acid‐caffeic acid conjugate isolated from T. farfara, was found to inhibit the activity of GalNAc‐T2.