pe
pep-04633 v1 CC-BY-SA-4.0

Beta-conglycinin blood-pressure-lowering peptide

A natural peptide that blocks ACE, the enzyme that raises blood pressure, helping to keep blood pressure in check. Experimental, not yet an approved drug.

statusbioassayed targetACE length10 aa refs3
angiotensin-converting-enzyme-ace-inhibitorsanti-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
ipTM0.739
pTM0.676
avg pLDDT86.6
ranking score0.841
STRUCTURE · PEP-04633 × ACE
ranking0.841
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence10 aa
1510
EDENNPFYLR
Hypotheses5 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 a shorter version of this soy-derived peptide block the enzyme that raises blood pressure more effectively than the original?

If true, a trimmed version of this peptide could be a more potent, gut-stable ingredient for blood-pressure-lowering foods or supplements. That would matter for the millions of people with mild hypertension who prefer dietary options over daily medication.

The hypothesis
Replacing the N-terminal acidic cluster EDENN with a single neutral linker such as Gly-Gly while retaining the C-terminal PFYLR pharmacophore increases ACE inhibitory potency by at least one order of magnitude and substantially improves proteolytic stability in simulated gastrointestinal conditions, because the bulky negative N-terminus currently reduces active-site complementarity and presents multiple peptide bonds susceptible to luminal proteases.
Why it’s plausible
The N-terminal EDENN segment contributes five residues (half the peptide) but likely does not directly contact ACE's catalytic zinc or key pharmacophore subsites. Its negative charge is repulsive relative to ACE's electropositive entry region. Additionally, E and D residues at the N-terminus are rapidly cleaved by gastric endoproteases and aminopeptidases, so the full 10-mer may be truncated in vivo before reaching the intestinal absorptive surface. Shorter ACE-inhibitor peptides from diverse food sources (VPP, IPP, LW, IW) with 2-5 residues and hydrophobic N-termini achieve IC50 values in the low micromolar range, far exceeding longer, negatively charged fragments. Swapping EDENN for GG would produce GG-PFYLR (7-mer), a length with documented oral absorption precedent and a neutral N-terminus that complements ACE surface electrostatics.
Why it matters
This hypothesis directly guides lead optimization: if true, a truncated GG-PFYLR analog derived from soy could be a more potent, orally bioavailable dietary antihypertensive candidate with a clear intellectual property position relative to the parent sequence.
Plausibility.59
Novelty.58
Impact.81
Basis · grounding2 papers · 1 computed/note
[1]
sequenceEDENN occupies positions 1-5 with negative charge; PFYLR occupies positions 6-10 and matches established ACE inhibitor pharmacophore patterns
[2]
paper
Stability of antihypertensive peptides in gastrointestinal environment is critical for in vivo efficacy; shorter peptides survive better
doi: 10.3168/jds.2016-11684
[3]
paper
Short di- and tripeptides VPP, IPP, LW, IW are among the most potent known food-derived ACE inhibitors; sequence features cited include hydrophobic and aromatic residues at C-terminus
doi: 10.1021/acs.jafc.8b02603
openupdated 2026-06-05

Could this peptide lower blood pressure without triggering the facial swelling risk linked to drugs that block two enzymes at once?

A past drug that blocked both enzymes caused dangerous swelling in some patients and was pulled from use. If this peptide naturally avoids that second enzyme, it could be a safer dietary route to blood pressure control, particularly for people who cannot tolerate certain medications.

The hypothesis
EDENNPFYLR inhibits ACE but not neprilysin (NEP/CD10), because the N-terminal acidic cluster prevents productive engagement with neprilysin's hydrophobic S1 and S1' subsites, conferring pathway-level selectivity within the renin-angiotensin system.
Why it’s plausible
Neprilysin (neutral endopeptidase) is a second major blood pressure-regulating metallopeptidase that cleaves natriuretic peptides and, like ACE, is a zinc endopeptidase. Combined ACE/NEP inhibition (as with omapatrilat) has been pursued clinically but causes excess bradykinin-related angioedema. Food-derived peptides that inhibit ACE but spare NEP would be safer dietary antihypertensives. Neprilysin's active-site subsites strongly favor hydrophobic residues at P1 and neutral/aromatic residues at P1'. The N-terminal EDE stretch of EDENNPFYLR would clash with NEP's preference for uncharged residues near its catalytic zinc, likely excluding EDENNPFYLR from productive NEP binding. The aromatic PFYLR tail would need to correctly orient, which the bulky charged N-terminus may prevent in the NEP geometry.
Why it matters
ACE-selective (NEP-sparing) inhibition avoids the angioedema risk associated with dual ACE/NEP inhibitors; confirming this selectivity would validate the peptide for functional food applications.
Plausibility.52
Novelty.62
Impact.71
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceEDE N-terminal cluster is negatively charged; NEP subsites prefer hydrophobic/neutral residues
[2]
sourceTraditional ACE inhibitors have side-effects from long-term use; natural peptides expected to have cleaner selectivity profiles
[3]
paper
Selectivity among cardiovascular enzyme targets is a key differentiator for food-derived antihypertensive peptides
doi: 10.2174/0929866529666220106100225
openupdated 2026-06-05

Is one specific amino acid acting as a structural hinge that holds the peptide in the right shape to do its job?

If this structural hinge is confirmed, researchers could design shorter, cheaper versions of the peptide that keep only the part that actually works. Shorter peptides tend to survive digestion better and are easier to deliver in food products.

The hypothesis
The proline at position 6 (P6) of EDENNPFYLR acts as a conformational hinge that stabilizes a bent backbone geometry placing the C-terminal FYLR tetrapeptide in the orientation required for zinc coordination in ACE, and truncating or replacing this proline with any other residue substantially reduces ACE inhibitory potency.
Why it’s plausible
Proline is the only amino acid that fixes the phi dihedral angle to around -60 degrees, imposing a rigid kink. In EDENNPFYLR, proline at position 6 separates the flexible acidic N-terminal segment from the aromatic C-terminal FYLR region. The literature repeatedly identifies proline as a key structural feature in antihypertensive peptides: proteinase K releases proline-enriched C-terminal fragments with high antihypertensive activity. ACE inhibitor studies consistently show that proline at P1' or P2 dramatically enhances binding via the induced-fit closure of the C-domain active site. The proline in EDENNPFYLR thus likely locks the FYLR tail into a productive conformation for ACE interaction, and its removal would produce a fully flexible decapeptide that cannot pre-organize optimally.
Why it matters
Identifying P6 as a conformational anchor constrains the minimal pharmacophore to the C-terminal half P-F-Y-L-R and justifies shorter analogs, reducing synthesis cost and improving oral bioavailability prospects.
Plausibility.58
Novelty.55
Impact.63
Basis · grounding2 papers · 1 computed/note
[1]
sequencePro at position 6 (P) divides acidic N-terminal EDENN from aromatic C-terminal FYLR; Pro is the sole residue with fixed backbone geometry
[2]
paper
Proteinase K generates proline-enriched C-terminal fragments with strong antihypertensive activity, supporting proline's structural role
doi: 10.1007/s12649-025-03430-w
[3]
paper
Proline and aromatic residues are specifically cited as structural features of potent antihypertensive peptides
doi: 10.1021/acs.jafc.8b02603
openupdated 2026-06-05

Could this peptide zero in on the part of the enzyme that raises blood pressure while leaving a blood-cell-regulating part untouched?

The enzyme it targets has two active regions with different jobs. Blocking only the one responsible for blood pressure, while leaving the other alone, could mean fewer off-target effects compared to standard ACE-inhibitor drugs. If this holds, the peptide would be a notably precise dietary ingredient.

The hypothesis
The C-terminal Arg residue of EDENNPFYLR confers selective binding to the C-domain active site of ACE over the N-domain active site, because ACE C-domain S2' pocket strongly prefers bulky basic residues at the substrate C-terminus whereas the N-domain is more tolerant of varied C-terminal residues.
Why it’s plausible
ACE is a two-domain zinc metallopeptidase. The C-domain and N-domain differ substantially in their S2' subsite preferences: the C-domain has a strong preference for C-terminal Arg or Lys, while the N-domain is less discriminating. EDENNPFYLR ends in Arg (R), which would be predicted to dock preferentially in the C-domain. C-domain-selective inhibition is therapeutically favorable because C-domain ACE activity dominates angiotensin II generation in vivo, while N-domain activity regulates hemoregulatory peptide AcSDKP. C-domain selectivity would thus lower blood pressure without disrupting AcSDKP-mediated bone marrow regulation, a side-effect concern with non-selective ACE inhibitors.
Why it matters
If C-domain selectivity is confirmed, EDENNPFYLR would belong to a small class of food-derived peptides with built-in domain selectivity, making it a safer dietary antihypertensive than non-selective small-molecule ACE inhibitors.
Plausibility.48
Novelty.57
Impact.77
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC-terminal Arg at position 10; C-domain S2' pocket strongly prefers basic residues
[2]
paper
ACE inhibitory mechanism through renin-angiotensin system described; ACE is monomeric with two active sites
doi: 10.1002/minf.201300131
[3]
paper
Antihypertensive peptides from food sources reviewed; domain-selective inhibition is a relevant differentiator
doi: 10.2174/0929866529666220106100225
openupdated 2026-06-05

Could the negatively charged end of this peptide be helping it dock in an unusual way that still blocks the blood-pressure enzyme?

Most known dietary blood-pressure peptides are short and oily-ended. This one breaks that pattern, and understanding why it still works could open a new design strategy for peptide ingredients, potentially allowing researchers to tune potency and selectivity in ways not possible with conventional short peptides.

The hypothesis
The N-terminal acidic cluster EDE of EDENNPFYLR acts as an electrostatic repulsion shield against the positively charged N-terminal region of ACE's substrate-binding cleft, causing the peptide to function as a competitive inhibitor with a distinct binding pose compared to classical short hydrophobic ACE-inhibitor peptides.
Why it’s plausible
Most potent food-derived ACE inhibitor peptides are short (2-7 residues) and enriched in hydrophobic residues, particularly with aromatic or proline C-termini. EDENNPFYLR is notably atypical in having a long negatively charged N-terminus (E-D-E-N-N). The active site of ACE has a positively charged entry region. A bulky negative N-terminal extension could shift the peptide's docking geometry, placing the PFYLR motif into the catalytic zinc-coordinating pocket while the EDE tail anchors outside the traditional binding groove. This altered pose could explain why the peptide retains activity despite its unusual charge distribution, and may produce a slower off-rate (tighter binding) or reduced susceptibility to proteolysis at the N-terminus in serum.
Why it matters
Understanding whether the negative N-terminal extension is a liability or an asset for ACE inhibition would guide rational truncation or extension strategies to optimize potency without losing selectivity.
Plausibility.55
Novelty.62
Impact.53
Basis · grounding2 papers · 1 computed/note
[1]
sequenceN-terminal E-D-E-N-N forms a negatively charged stretch uncommon in short food-derived ACE inhibitors; C-terminal P-F-Y-L-R matches the aromatic-proline motif common in potent ACE inhibitors
[2]
paper
Review notes proline and aromatic amino acids are common features of potent antihypertensive peptides; longer fragments with different charge distributions are also active in vivo
doi: 10.1021/acs.jafc.8b02603
[3]
paper
ACE substrate-binding cleft properties relevant to inhibitor docking described
doi: 10.1002/minf.201300131
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.7388739585876465 boltz-2
ranking score 0.8406808972358704 boltz-2
structural qualityopenfold3
metricvaluenote
gpde1.173global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Glu-Asp-Glu-Asn-Asn-Pro-Phe-Tyr-Leu-Arg
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). Beta-conglycinin blood-pressure-lowering peptide (pep-04633, v1). PeptideModel. https://peptidemodel.com/card/pep-04633
@peptide{pep04633,
  sequence = {EDENNPFYLR},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
references 3 papers
discussion no comments
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