Heterologous Expression, Antihypertensive Effect, and Underlying Mechanism of Sequence-Designed ACE Inhibitory Peptide YWLKP.
TL;DR
YWLKP is supported as a promising antihypertensive candidate for functional food applications after being systematically investigated by biotechnological preparation, biolayer interferometry, molecular dynamics simulation, and studies on spontaneously hypertensive rats (SHRs).
Abstract
Rational sequence optimization is essential for transforming food-derived peptides into more potent angiotensin-converting enzyme (ACE) inhibitors. LYPVK and its sequence-designed derivative YWLKP exhibit potent activity; however, their binding mechanisms, transport routes, and in vivo antihypertensive effects remain unclear. Here, they were systematically investigated by biotechnological preparation, biolayer interferometry (BLI), molecular dynamics (MD) simulation, Caco-2 transport assays, and studies on spontaneously hypertensive rats (SHRs). BLI revealed that YWLKP bound to ACE with a subnanomolar affinity constant KD of (1.08 ± 0.40) × 10-9 M, consistent with MD results showing a more stable peptide-ACE complex. Caco-2 monolayer transport showed that LYPVK mainly permeated via the paracellular pathway, whereas YWLKP exhibited PepT1-mediated transport. In SHRs, both peptides significantly reduced blood pressure after single and long-term administration, accompanied by renin-angiotensin system modulation, reduced renal and cardiac impairment, and improved endothelial dysfunction. Collectively, these findings support YWLKP as a promising antihypertensive candidate for functional food applications.