Corosolic acid and its derivatives targeting MCCC1 against insulin resistance and their hypoglycemic effect on type 2 diabetic mice.

Corosolic acid (CA), a natural triterpenoid, exhibits various biological activities and is often called as plant-derived insulin due to its significant hypoglycemic effects, making it especially beneficial for individuals with diabetes or high blood glucose levels. However, CA has notable in vitro toxicity, low water solubility, and poor pharmacokinetic properties. To address these limitations, a series of CA derivatives were synthesized, resulting in the identification of derivative H26, which demonstrates a significantly enhanced hypoglycemic effect, reduced toxicity, and improved pharmacokinetic characteristics compared to CA. To identify the target protein of CA and investigate its therapeutic potential, a chemical probe derived from natural products, called CA-biotin, was designed and synthesized. By employing an avidin-biotin affinity binding system, we distinguished the differential protein bands between CA-biotin and biotin. This quantitative proteomic analysis revealed, for the first time, that the biotin-containing enzyme methylcrotonoyl-CoA carboxylase 1 (MCCC1) directly binds to CA. The interaction between H26 and MCCC1 was examined in vitro. The research on the mechanisms by which CA and H26 address Type 2 diabetes mellitus (T2DM) focused on the insulin resistance signaling pathway, specifically targeting MCCC1. The results indicated that H26 shows significant promise as a potential hypoglycemic agent, while MCCC1 may serve as a valuable target for addressing insulin resistance. This presents a promising opportunity for developing new medications aimed at improving the health of patients with type 2 diabetes mellitus (T2DM) or hyperglycemia.