A paper entitled "Exploring and applying the substrate promiscuity of a C-glycosyltransferase in the chemo-enzymatic synthesis of bioactive C-glycosides" was published online in Nature Communications on October 14, 2020. The research leading by Prof. Jungui Dai from the State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, cooperated with Prof. Fei Ye from Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study reported the discovery and characterization of a C-glycosyltransferase derived from Aloe vera, which can effectively C-glycosylate aromatic phenolic compounds without acyl group. Some new C-glycosides with good SGLT2 inhibitory activity and selectivity were chemo-enzymatically synthesized. This study is of great significance in the discovery and green synthesis of innovative drugs for anti-diabetes.
C-linked sugar moiety is an essential pharmacodynamic group for many kinds of clinical drugs and bioactive natural products. However, chemical C-glycosylation is faced with the challenges of poor selectivity, group protection and deprotection, with long route and high cost. Dai's group discovered a C-glycosyltransferase (AbCGT) from A. vera by using transcriptomics, which can efficiently catalyze the C-glycosylation of a variety of acyl free aromatic aglycones. Some new aglycons were synthesized in one step by chemical method, and then C-linked sugar moiety was selectively introduced by enzymatic method. Ye's group studied the biological activity and action characteristics of the C-glycosides on the molecular target of SGLT2 and found 16 novel C-glycosides with strong SGLT2 inhibitory activity, and investigated the structure-activity relationship. Through further evaluation of the inhibitory activity of SGLT2 with three animal models in vivo, a new C-glucoside with drug development potential was hit. On this basis, the researchers constructed a whole cell catalytic synthesis system, and the theoretical yield of target active C-glucoside was 3.95 g/L. This study not only provides a direction for the practical application of C-glycosyltransferase, but also provides a leading compound for the discovery of antidiabetic drugs.
Fig. 1. Chemo-enzymatic synthesis of antidiabetic C-glycosides
