Identification of a novel ACLY inhibitor proanthocyanidin B2 from grape seeds with lipid-lowering effect in vitro

ATP citrate lyase (ACLY) is a crucial enzyme in glycolipid metabolism. To date, only its one prodrug bempedoic acid has been approved. The discovery of direct ACLY inhibitors is important for developing new lipid-lowering drugs. Grape seeds, used in functional foods and medicines, have lipid-lowering efficacy. However, it remains unknown whether their components directly inhibit ACLY. To investigate it, a multi-component screening method was used and proanthocyanidin B2 was identified as a novel ACLY inhibitor with an IC 50 value of 2.73 μM. Differential scanning fluorimetry confirmed its directly binding to ACLY. Proanthocyanidin B2 acted as a noncompetitive inhibitor in kinetic studies and bound stably with ACLY in molecular dynamics simulations. In vitro , proanthocyanidin B2 reduced lipid accumulation via inhibiting key transcription factors associated with ACLY. This study revealed a novel ACLY inhibitor contributing to lipid-lowering efficacy of grape seeds and provided a unique scaffold for ACLY drug design.