Pseudoheterins A-J, cyclic peptides from Pseudostellaria heterophylla and their potential as antidiabetic agents targeting α-glucosidase.

The LC-MS-guided phytochemical investigation of Pseudostellaria heterophylla, combined with the TLC analysis using ninhydrin as a detection reagent, led to the isolation of 21 cyclic peptides (1-21), including 10 undescribed ones (1-10). Their structures were elucidated via extensive spectroscopic analysis, LC-MS/MS, solid-phase synthesis, and Marfey's method. The obtained cyclic peptides were evaluated for their α-glucosidase inhibitory activities. Compounds 2, 10, 12, 15, and 17 exhibited α-glucosidase inhibitory effects comparable to those of the positive control acarbose. Among them, compound 2 exhibited the most potent activity, even superior to that of acarbose. Molecular docking of 2 with α-glucosidase was performed to explore its binding mode. In a zebrafish model, compound 2 effectively reduced glucose levels, regulated the expression of key metabolic genes (PEPCK, GCK, and SDHDB), and exhibited no obvious toxicity toward human cell lines or zebrafish at the tested concentrations. These results identify 2 as a potential lead compound for the development of new natural antidiabetic agents.