pe
pep-04705 v1 CC-BY-SA-4.0

Blood-pressure-lowering peptide (LKKYKVPQ)

A small peptide that blocks ACE, the enzyme that raises blood pressure, helping to keep blood pressure in check; used only as a lab research tool.

statusbioassayed targetACE length8 aa refs2
anti-hypertensive
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 2 / 5 · 0 verified on platform
prediction metrics boltz-2 1.0
ipTM0.743
pTM0.559
avg pLDDT90.4
ranking score0.871
STRUCTURE · PEP-04705 × ACE
ranking0.871
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence8 aa
158
LKKYKVPQ
Hypotheses6 directions▾ collapse

Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.

openupdated 2026-06-05

Could changing a single piece of this peptide make it dramatically more effective against high blood pressure?

If this holds, researchers could upgrade a natural milk-derived compound into a much more potent blood pressure lowering agent with minimal changes, keeping it food-safe and potentially cheaper to produce. This would matter for people seeking dietary supplements or functional foods as alternatives to prescription drugs.

The hypothesis
Substituting the C-terminal glutamine (Q8) of LKKYKVPQ with leucine or phenylalanine would increase ACE inhibitory potency by at least one order of magnitude, because hydrophobic or aromatic residues at the terminal position better fill the S1' subsite of ACE compared to the polar glutamine.
Why it’s plausible
The S1' subsite of human somatic ACE is a hydrophobic pocket lined by Phe512, Val518, and Val380. Glutamine at Q8 provides a polar amide side chain that makes suboptimal contacts with this hydrophobic environment. Known potent ACE inhibitor peptides terminating in leucine (L), phenylalanine (F), or proline (P) routinely achieve IC50 values in the sub-micromolar range, while polar-terminus variants are weaker. The otherwise well-structured VPQ pharmacophore means the only targeted substitution needed is Q8. This is a minimal, testable single-residue change.
Why it matters
A single-point engineering rule confirmed for this scaffold would provide a rapid, low-cost route to a significantly more potent antihypertensive peptide while retaining the food-protein origin and the favorable cationic N-terminus, accelerating optimization of casein-derived therapeutics.
Plausibility.68
Novelty.50
Impact.63
Basis · grounding2 papers · 1 computed/note
[1]
paper
Structure-function studies establish that amino acid identity at terminal positions directly governs ACE inhibitory potency of food-derived peptides.
doi: 10.1021/jf5002606
[2]
sequenceC-terminal Q8 is a polar residue; substitution to L or F would convert it to a hydrophobic terminal matching the ACE S1' preference seen in potent benchmark inhibitors.
[3]
paper
Blood pressure reduction in SHR is used as the in vivo readout for peptide potency; structure-activity optimization guided by ACE binding is the standard design approach.
doi: 10.1016/j.foodchem.2017.02.039
openupdated 2026-06-05

Could one peptide from milk do two useful jobs: lower blood pressure and kill bad bacteria?

If both effects are real, people with high blood pressure linked to poor gut health, a common pairing in metabolic syndrome, might benefit from a single food-derived compound that addresses both problems. It could inform the design of functional foods or supplements that do more than one thing without added complexity.

The hypothesis
The N-terminal LKK tripeptide of LKKYKVPQ confers a secondary antimicrobial mechanism through electrostatic binding to anionic bacterial membranes, independent of the C-terminal ACE-inhibitory pharmacophore, making the peptide bifunctional.
Why it’s plausible
The second reference documents broad-spectrum antimicrobial activity and membrane disruption (propidium iodide uptake) for a bovine alphaS1-casein-derived peptide. LKKYKVPQ contains three cationic residues (K2, K4, K6) within eight amino acids, giving a high positive charge density (net +3 at physiological pH) typical of membrane-active antimicrobial peptides. The LKK sequence at the N-terminus resembles cationic stretches in known AMPs. The C-terminal VPQ is hydrophobic enough to participate in membrane insertion. These two functional segments are spatially distinct within an 8-mer, suggesting each acts independently.
Why it matters
A single food-grade peptide with dual ACE-inhibitory and antimicrobial activity would be valuable in functional food contexts where gut dysbiosis accompanies metabolic syndrome, and might reduce blood pressure through both systemic ACE inhibition and modulation of gut microbiota.
Plausibility.53
Novelty.57
Impact.58
Basis · grounding2 papers · 1 computed/note
[1]
paper
Casein-derived peptide Cp1 from the same parent protein class demonstrates broad-spectrum antimicrobial activity and membrane disruption in E. coli; flow cytometry with propidium iodide confirms membrane damage.
doi: 10.3390/molecules23051220
[2]
sequenceNet charge +3 from K2, K4, K6; three cationic residues in 8-mer is above the threshold density seen in short AMPs.
[3]
paper
E. faecalis proteolysis of bovine skim milk generates the parent peptide in a fermentation context where microbial activity is relevant.
doi: 10.1016/j.ijfoodmicro.2013.06.019
openupdated 2026-06-05

Does this peptide survive digestion, or does the gut break it down into something that still works?

If digestion releases a smaller, stable fragment that still lowers blood pressure, it would suggest the body is doing the work of activating the compound automatically. That could mean a simpler, cheaper ingredient (a tiny tripeptide rather than the full octapeptide) would be enough, making oral supplements more practical and cost-effective.

The hypothesis
LKKYKVPQ retains significant ACE-inhibitory activity after simulated gastrointestinal digestion by pepsin and pancreatin, because the C-terminal VPQ segment is released as a stable sub-fragment that independently inhibits ACE.
Why it’s plausible
The axis-hit literature notes that low-molecular-weight peptides from food can retain bioactivity after gastrointestinal digestion. LKKYKVPQ contains multiple trypsin/chymotrypsin cleavage sites (after K2, K4, Y5, K6), suggesting the peptide would be rapidly cleaved. However, the C-terminal VPQ tripeptide would be expected to survive as a terminal fragment because its penultimate proline resists peptidase cleavage. VPP and IPP, which have the same core motif, are orally bioactive. If VPQ is the active fragment, the octapeptide could function as a pro-drug releasing a potent tripeptide in the gut lumen.
Why it matters
If the VPQ tripeptide is the active species in vivo, it would redirect drug development from the octapeptide to the simpler, cheaper tripeptide, and simultaneously explain why food-fermentation peptides with diverse N-terminal sequences converge on similar antihypertensive activity when administered orally.
Plausibility.50
Novelty.50
Impact.65
Basis · grounding2 papers · 1 computed/note
[1]
paper
Literature states bioactivity of low-molecular-weight peptides can be retained during gastrointestinal digestion; in vivo effects of identified active peptides remain to be confirmed.
doi: 10.1038/s41598-021-84820-7
[2]
paper
ACE inhibitory peptides must reach the cardiovascular system in an active form to lower blood pressure; transit through the gut is the key barrier.
doi: 10.1079/bjn20041189
[3]
sequenceK at positions 2, 4, 6 and Y at position 5 are cleavage sites for trypsin and chymotrypsin; the C-terminal VPQ contains a proline that resists carboxypeptidase cleavage.
openupdated 2026-06-05

Does this peptide work on blood pressure the same way as the already-studied ones from fermented milk?

If the binding mechanism matches what is already known from validated peptides, it would confirm this compound belongs to a trusted class of natural blood pressure agents and give developers a clear roadmap for refining it. For consumers, it would add confidence that the effect is real and the science is solid.

The hypothesis
LKKYKVPQ inhibits ACE (angiotensin-converting enzyme, somatic isoform) primarily through its C-terminal VPQ motif, which engages the enzyme's S1/S2' subsites in a manner analogous to established tripeptide inhibitors such as VPP and IPP, yielding a competitive inhibition mode.
Why it’s plausible
The C-terminal proline at position 7 (VPQ) mirrors the pharmacophore shared by validated food-derived ACE inhibitors VPP and IPP. Proline at the penultimate C-terminal position shields the peptide bond from ACE's carboxypeptidase cleavage and positions the terminal residue (Q) in the S1' pocket. The peptide's origin from bovine casein via lactic acid bacterial proteolysis parallels the biosynthetic route of VPP and IPP. The null target annotation in the card suggests ACE has not been formally confirmed for this specific sequence, making the mode-of-binding claim testable.
Why it matters
Confirming ACE as the primary target and mapping the VPQ pharmacophore would validate structure-activity rules for casein-derived inhibitors and establish whether the longer flanking sequence (LKKY) contributes to or detracts from potency relative to minimalist tripeptide inhibitors.
Plausibility.57
Novelty.32
Impact.55
Basis · grounding2 papers · 1 computed/note
[1]
paper
Peptide isolated from E. faecalis-fermented bovine skim milk hydrolysate with measured ACE-inhibitory activity; broader context confirms casein-derived ACE-IP production by LAB strains.
doi: 10.1016/j.ijfoodmicro.2013.06.019
[2]
sequenceC-terminal VPQ contains proline at penultimate position, matching the pharmacophore of benchmark ACE inhibitors VPP and IPP.
[3]
paper
Food-derived ACE inhibitory peptides shown effective in SHR in vivo despite weaker in vitro IC50 than drugs, consistent with LKKYKVPQ's expected profile.
doi: 10.1271/bbb.59.425
openupdated 2026-06-05

Could a long-term blood pressure supplement from milk avoid the reproductive side effects that concern some researchers?

Some compounds that block the same blood pressure enzyme have been linked to reduced male fertility in animal studies. If this peptide turns out to be selective enough to avoid that pathway, it would be a safer option for men taking it regularly as a dietary supplement, removing a key safety concern from the development path.

The hypothesis
LKKYKVPQ selectively inhibits the somatic ACE isoform over the testicular (germinal) ACE isoform because its C-terminal glutamine (Q) and the flanking lysine-rich sequence sterically disfavor binding to the single active site of germinal ACE.
Why it’s plausible
Somatic ACE has two homologous zinc-metallopeptidase domains (N and C); germinal ACE contains only the C-domain. Several food peptides show domain selectivity based on C-terminal residue identity and upstream sequence. The polar, bulky Q at the C-terminus of LKKYKVPQ and the adjacent K6 create a distinct electrostatic environment. Isoform selectivity matters clinically because germinal ACE inhibition is associated with reduced male fertility, a concern for long-term use of ACE-targeted nutraceuticals.
Why it matters
Demonstrating isoform selectivity would de-risk reproductive safety concerns for this peptide as a dietary supplement ingredient and provide structural insights into domain-selective inhibition rules for food-derived ACE inhibitors.
Plausibility.35
Novelty.53
Impact.50
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC-terminal Q (glutamine) is an uncommon residue at position 8 among benchmark ACE inhibitors; the +3 charge from surrounding lysines creates a unique electrostatic context near the pharmacophoric VPQ.
[2]
paper
Ethnic and conformational differences in ACE inhibitory peptide responses suggest structural determinants beyond simple VPP-type pharmacophore govern potency and selectivity.
doi: 10.1021/acs.jafc.8b02603
[3]
paper
ACE inhibitory peptides influence cardiovascular, endocrine, immune, and nervous systems, implying off-target potential that isoform selectivity could mitigate.
doi: 10.1016/j.foodchem.2012.08.080
openupdated 2026-06-05

Does this peptide latch onto its blood pressure target in two places at once, making it more effective than a shorter version would be?

If a specific pair of amino acids in the middle of the peptide acts as a second anchor to the enzyme, it would explain why the full-length version might outperform shorter fragments. For developers, it would give a clear design rule for building more effective blood pressure peptides from food proteins.

The hypothesis
The tandem tyrosine-lysine motif (YK at positions 5-6) in LKKYKVPQ contributes to ACE inhibitor potency by acting as a secondary anchor through pi-cation and hydrogen-bond interactions with ACE active site residues, distinct from the C-terminal pharmacophore.
Why it’s plausible
Tyrosine has hydroxyl and aromatic groups capable of H-bonding and pi-stacking, while the adjacent lysine provides a cation that can form pi-cation interactions with aromatic active-site residues (e.g., Tyr523, Phe457 in ACE). Among ACE inhibitor peptides, those with aromatic or bulky hydrophobic residues at internal positions tend to have lower IC50 values than purely aliphatic sequences of comparable length. LKKYKVPQ contains Y at position 5 immediately upstream of K6 and the pharmacophoric VPQ, creating a potential dual-anchor binding mode: VPQ in the primary S1/S2 subsite, and YK in an upstream pocket. The sequence LKKY at positions 1-4 includes a second YK-like sub-motif (KY at 3-4) that could further reinforce binding.
Why it matters
Identifying the YK motif as a secondary anchor would explain why LKKYKVPQ may be more potent than the VPQ tripeptide alone, and would provide a design rule for engineering longer, higher-affinity food-derived ACE inhibitors by preserving or extending this internal motif.
Plausibility.35
Novelty.48
Impact.50
Basis · grounding2 papers · 1 computed/note
[1]
paper
Structure-function studies of blood-pressure-lowering peptides indicate amino acid composition and sequence govern antihypertensive activity; aromatic and hydrophobic residues at internal positions enhance ACE inhibition.
doi: 10.1021/jf5002606
[2]
sequenceSequence contains Y at position 5 flanked by K4 and K6, creating a YK sub-motif adjacent to the C-terminal VPQ pharmacophore; a second KY sub-motif is present at positions 3-4.
[3]
paper
Peptides with IC50 in the low micromolar range are expected to be effective in vivo; the structural determinants of potency beyond C-terminal proline warrant investigation.
doi: 10.1021/jf100977z
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.7433778047561646 boltz-2
ranking score 0.8714852333068848 boltz-2
structural qualityopenfold3
metricvaluenote
gpde0.999global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Leu-Lys-Lys-Tyr-Lys-Val-Pro-Gln
recipeboltz-2 1.0
parametervalue
modelboltz-2 1.0
weights
hardwarenvidia_nim_api
mlx version
python
random seed
msa strategynone
diffusion samples1
runtime
predicted bymlx@peptide
predicted at2026-04-24
citationbibtex
peptidemodel (2026). Blood-pressure-lowering peptide (LKKYKVPQ) (pep-04705, v1). PeptideModel. https://peptidemodel.com/card/pep-04705
@peptide{pep04705,
  sequence = {LKKYKVPQ},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
references 2 papers
discussion no comments
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