Multitarget Amaranth Peptides: ACE Inhibition, ACE2 Modulation, and Bioavailability Assessment

Hypertension, a major risk factor for cardiovascular disease, is largely regulated by the renin-angiotensin system (RAS). This study evaluates the multitarget potential of three amaranth-derived peptides -SFNLPILR, FNLPILR, and AFEDGFEWVSFK- previously identified as renin inhibitors. We assessed their ability to inhibit angiotensin-converting enzyme (ACE), modulate ACE2 activity, and their bioavailability. In vitro assays demonstrated that SFNLPILR and FNLPILR are potent ACE inhibitors (IC₅₀ = 0.075 and 0.055 mM, respectively), with selective or minimal modulation of ACE2 enzymatic activity. Bioinformatic analysis identified encrypted bioactive motifs with known ACE -inhibitory activity within their sequences. Molecular docking revealed that both peptides interact with ACE's catalytic residues through the LR motif. Additionally, transepithelial transport studies using Caco-2 monolayers confirmed that peptide fragments can cross the intestinal barrier. These findings position SFNLPILR and FNLPILR as promising multifunctional candidates for the development of functional foods aimed at reducing hypertension risk via RAS modulation.