Wei-Ting Hung, Hsien-Yu Liao, Christoper Caesar Yudho Sutopo, Endrika Widyastuti, Tim Chi-Chen Lin, Jue-Liang Hsu
Hypertension, a major risk factor for cardiovascular diseases, remains a leading global health concern and has prompted growing interest in angiotensin-converting enzyme (ACE) inhibitory peptides from plant seeds as promising nutraceutical ingredients. To our knowledge, this is the first study to identify antihypertensive peptides from Perilla frutescens seed protein, with thermolysin hydrolysate demonstrated the favorable ACE-inhibitory (ACEI) activity (IC50 = 141 µg/mL). Two parallel bioassay-guided fractionations (SCX and RP-HPLC) were used to screen the fractions with the best ACEI activity, from which two novel tetrapeptides, TLVY (TY4) and LLVY (LY4), were identically found. Both peptides exhibited notable ACEI activities with IC50 values of 31 µM and 44 µM, respectively. Enzyme kinetics showed that TY4 and LY4 antagonized ACE via a competitive inhibition mechanism, while molecular docking revealed specific interactions with canonical catalytic residues of ACE through hydrogen bonding. The structural characteristics and bioactivity profiles of TY4 and LY4 support their potential as naturally derived antihypertensive agents. This study highlights the discovery of novel tetrapeptides from Perilla frutescens seeds with ACE inhibitory activity, providing a foundation for the development of functional foods targeting hypertension. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025.
Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan; Department of Animal Science and Technology, National Taiwan University, Taipei, Taiwan; Department of Food Science and Biotechnology, Faculty of Agricultural Technology, Universitas Brawijaya, Malang, Indonesia; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan
