pe
pep-04741 v1 CC-BY-SA-4.0

Blood-pressure-lowering peptide (EGPKLVAS)

A small peptide that blocks ACE, an enzyme that raises blood pressure, used only as a lab research tool.

statusbioassayed targetACE length8 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
ipTM0.837
pTM0.777
avg pLDDT89.6
ranking score0.884
STRUCTURE · PEP-04741 × ACE
ranking0.884
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence8 aa
158
EGPKLVAS
Hypotheses7 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 reshaping this peptide into a closed loop stop stomach enzymes from breaking it down before it works?

Most food-derived blood-pressure peptides fall apart in the gut before they can act. If this chemical modification holds up in testing, it could mean a more effective oral supplement or drug that works at a lower dose, for people managing hypertension.

The hypothesis
Cyclization of EGPKLVAS through a lactam bridge between the Glu1 side-chain carboxylate and the Lys4 epsilon-amine would generate a conformationally constrained analog with enhanced proteolytic stability and comparable or improved ACE inhibitory potency relative to the linear peptide.
Why it’s plausible
The sequence contains Glu at position 1 and Lys at position 4, which are exactly three residues apart. This spacing is geometrically compatible with a side-chain-to-side-chain lactam bridge that would create a cyclic (i+3) constraint. Such cyclizations in food-derived antihypertensive peptides have not been widely explored but are established as a strategy for improving serum stability and resistance to aminopeptidases, which are the primary enzymes degrading N-terminal residues. The proteolytic-stability axis hits from 10.1248/cpb.c25-00478 confirm that stabilization strategies are mechanistically justified, and the manufacturing axis confirms that the 8-residue length is fully compatible with SPPS for analog synthesis.
Why it matters
A cyclic EGPKLVAS analog could overcome the major translational barrier for food-derived antihypertensive peptides, namely poor stability in the gastrointestinal tract, potentially enabling effective oral dosing at lower peptide mass.
Plausibility.62
Novelty.52
Impact.57
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceGlu at position 1 and Lys at position 4 are i to i+3, the correct spacing for a stable side-chain lactam bridge
[2]
sourceD-amino acid substitution and analogous modifications improve proteolytic stability; side-chain cyclization acts via the same mechanism of blocking protease recognition
[3]
paper
Oral bioavailability axis hit documents the GI degradation problem as the central challenge for oral peptide drug development
doi: 10.1038/s41392-024-02107-5
openupdated 2026-06-05

Does this peptide work on a second enzyme that current testing has missed, giving it a stronger effect on blood pressure?

A peptide that inhibits two separate blood-pressure pathways at once could be more potent than one acting alone. If confirmed, this could make it a candidate food-derived alternative to combination drugs, for people looking for natural cardiovascular support.

The hypothesis
In addition to ACE, EGPKLVAS inhibits neprilysin (NEP/CD10), a zinc metallopeptidase that shares structural homology with ACE and degrades natriuretic peptides, thereby providing a dual antihypertensive mechanism not captured by the current single-target annotation.
Why it’s plausible
Neprilysin and ACE are both zinc-dependent metallopeptidases with partially overlapping peptide substrate preferences. Several food-derived short peptides have been found to inhibit both enzymes, a property of growing pharmaceutical interest after sacubitril/valsartan demonstrated the clinical value of combined neprilysin-ACE inhibition. The current target annotation is null, suggesting the molecular targets have not been fully characterized. EGPKLVAS contains the sequence motif G-P at positions 2-3, which is present in several known neprilysin substrates, and the hydrophobic cluster L-V at positions 5-6 may fit the NEP S1 hydrophobic pocket.
Why it matters
A dual ACE/NEP inhibitor would represent a functionally more potent antihypertensive scaffold than ACE inhibition alone, with potential to be developed as a food-derived analog of the sacubitril pharmacophore.
Plausibility.45
Novelty.62
Impact.72
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceG-P at positions 2-3 and L-V at positions 5-6 match structural features tolerated in neprilysin active site
[2]
paper
Review of food-derived antihypertensive peptides for cardiovascular disease management, context in which dual-target activity is an active research frontier
doi: 10.2174/0929866529666220106100225
[3]
structureBoltz-2 structure prediction was computed; the null target annotation means no docking to NEP has been attempted
openupdated 2026-06-05

Could stomach enzymes chew off the first building block of this peptide and release a stronger fragment that does the real work?

If this peptide turns out to be a precursor that gets activated during digestion rather than degraded, it would mean lab measurements of its potency are actually underestimates. That would change how researchers dose and formulate it, which matters for anyone developing it as a supplement or drug.

The hypothesis
The glutamate (E) at position 1 of EGPKLVAS functions as a prodrug-like N-terminal anchor that is cleaved by gastrointestinal enzymes to release a shorter active fragment (GPKLVAS or PKLVAS) with higher ACE inhibitory potency than the intact octapeptide.
Why it’s plausible
Several food-derived antihypertensive peptides are known to be prodrugs: the intact form has modest ACE IC50 but gastrointestinal proteases release shorter fragments that are the true pharmacophore. The 10.1079/bjn20041189 axis hit states explicitly that blood-pressure-lowering requires ACE-inhibitory peptides to reach the cardiovascular system in an active form, implying the relationship between ingested and circulating forms can differ. Glutamate at the N-terminus provides a site for aminopeptidase action, and the resulting PKLVAS sequence would have a proline at position 1, a configuration that strongly resists further N-terminal degradation and is highly represented among potent ACE inhibitors.
Why it matters
If EGPKLVAS is a prodrug, its apparent in vitro IC50 underestimates its in vivo antihypertensive effect; formulation and dosing strategies should target gastrointestinal conversion rather than preventing peptide degradation.
Plausibility.52
Novelty.50
Impact.62
Basis · grounding2 papers · 1 computed/note
[1]
sequenceRemoval of N-terminal E by aminopeptidase would generate PKLVAS, placing Pro at position 1 where it blocks further N-terminal cleavage
[2]
paper
States that ACE-inhibitory peptides must reach cardiovascular system in active form, implying metabolic conversion is a key variable
doi: 10.1079/bjn20041189
[3]
paper
Notes that the active form in the organism may correspond to shorter fragments generated from longer precursor sequences
doi: 10.1021/acs.jafc.8b02603
openupdated 2026-06-05

Beyond lowering blood pressure, could this peptide also reduce the vessel wall inflammation that drives heart disease?

Vascular inflammation is an early step toward atherosclerosis and heart attacks, even in people without high blood pressure. If this peptide can reduce that inflammation through its known mechanism, it could be useful for a much wider group, including people in early-stage metabolic or cardiovascular risk.

The hypothesis
EGPKLVAS reduces endothelial inflammation independently of blood-pressure lowering by inhibiting ACE-mediated conversion of angiotensin I to angiotensin II, thereby suppressing AT1R-mediated NF-kB activation and downregulating adhesion molecule expression (VCAM-1, ICAM-1) in vascular endothelium.
Why it’s plausible
Angiotensin II, the direct product of ACE catalysis, activates AT1R to drive NF-kB-dependent inflammatory gene expression in endothelial cells, including upregulation of VCAM-1 and ICAM-1 that recruit monocytes to atherosclerotic lesions. This mechanism is pharmacologically relevant independently of blood pressure: ACE inhibitors reduce cardiovascular events partly through pleiotropic anti-inflammatory effects. An 8-residue food-derived ACE inhibitor reaching the endothelium could attenuate vascular inflammation in pre-hypertensive or normotensive subjects with elevated inflammatory risk. The selectivity axis hit from 10.1016/j.foodchem.2012.08.080 specifically notes the broader cardiovascular functions of antihypertensive peptides beyond blood pressure.
Why it matters
Demonstrating anti-inflammatory activity in endothelial cells would open a repurposing path for EGPKLVAS in early atherosclerosis or metabolic syndrome, expanding the target indication beyond hypertension management.
Plausibility.55
Novelty.23
Impact.48
Basis · grounding3 papers
[1]
paper
Notes peptides with antihypertensive effects also influence cardiovascular, endocrine, immune, and nervous system physiology
doi: 10.1016/j.foodchem.2012.08.080
[2]
paper
Reviews applications of food-derived antihypertensive peptides for cardiovascular disease management, including inflammatory pathways
doi: 10.2174/0929866529666220106100225
[3]
paper
Notes that hemodynamic parameters beyond blood pressure, including endothelial function, have been improved by antihypertensive food peptides
doi: 10.1021/acs.jafc.8b02603
openupdated 2026-06-05

Does this peptide bind to the particular part of the ACE enzyme that could give it a cleaner safety profile than common blood-pressure drugs?

Some ACE inhibitors cause a persistent dry cough because they act on the wrong part of the enzyme. If this peptide turns out to bind only the preferred part, it could potentially avoid that side effect, which would be meaningful for patients who cannot tolerate standard ACE inhibitor medications.

The hypothesis
EGPKLVAS inhibits ACE primarily through interaction with the S1 and S2 subsites of the ACE C-domain active site, where the C-terminal valine-alanine-serine triplet engages the zinc-coordinating pocket in a manner analogous to known food-derived ACE-inhibitory peptides bearing small aliphatic C-termini.
Why it’s plausible
The ACE C-domain preferentially accommodates peptides with hydrophobic or small aliphatic residues at the C-terminus. EGPKLVAS ends in V-A-S, where Val fits the S1' lipophilic pocket and Ala fits S2'. The proline at position 3 imposes a conformational constraint that may preorganize the peptide backbone for productive binding, consistent with the well-documented prevalence of proline in potent food-derived ACE inhibitors cited in the 10.1021/acs.jafc.8b02603 review. The null target annotation suggests this interaction has not been formally mapped to a domain.
Why it matters
Confirming C-domain selectivity would distinguish EGPKLVAS from N-domain-preferring inhibitors, affecting its predicted side-effect profile (C-domain-selective inhibitors avoid bradykinin accumulation associated with dry cough).
Plausibility.42
Novelty.33
Impact.57
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC-terminal residues V-A-S and internal Pro at position 3 match structural features of known ACE-inhibitory peptide pharmacophores
[2]
paper
Review notes common features of antihypertensive peptides include proline and hydrophobic residues; peptides with 5-7 residues confirmed in vivo
doi: 10.1021/acs.jafc.8b02603
[3]
paper
Tagged as ACE inhibitor but target field is null, indicating mechanistic mapping is incomplete
doi: 10.2174/1389557518666180424110754
openupdated 2026-06-05

Does one unusually flexible amino acid in the middle of this peptide act as a pivot that lets the whole chain fold into the right shape for binding?

If one building block controls the peptide's folding into an active shape, chemists could replace it with a version that locks that shape permanently. That could improve both potency and stability, which is a step toward turning a food-derived peptide into a practical drug candidate.

The hypothesis
The glycine at position 2 of EGPKLVAS acts as a conformational hinge that allows the peptide backbone to adopt a bent geometry presenting the proline-lysine segment to the ACE active site, and substituting glycine with alanine at this position reduces ACE inhibitory potency by more than 50%.
Why it’s plausible
Glycine is the only amino acid without a side chain, conferring backbone dihedral angle freedom not available to other residues. In an 8-residue peptide, the E-G junction at positions 1-2 would allow the N-terminal glutamate to swing away from the binding groove, positioning G-P-K as a structural tripeptide presenting key pharmacophoric elements. This type of Gly-mediated flexibility has been described for other short bioactive peptides. The prediction (Boltz-2) computed a 3D structure but its interface confidence with an annotated target is uninformative given the null target; the backbone geometry is still a valid data point.
Why it matters
Identifying Gly2 as a conformational hinge provides a rational basis for peptidomimetic design: replacing Gly with N-methylglycine (sarcosine) would lock the preferred conformation and potentially increase both potency and proteolytic resistance.
Plausibility.43
Novelty.43
Impact.43
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceGly at position 2 between Glu and Pro; Gly is the only residue allowing full backbone flexibility at this position
[2]
structureBoltz-2 structure prediction provides a 3D backbone model of the peptide that reflects this geometry
[3]
paper
Notes paucity of structure-function information for blood-pressure-lowering peptides and calls for studies on amino acid composition and sequence effects on activity
doi: 10.1021/jf5002606
openupdated 2026-06-05

Does the electric charge of this peptide steer it toward only one of the two working ends of the ACE enzyme, avoiding the side that interferes with other body processes?

ACE inhibitor drugs work on both halves of their target enzyme, and one half is linked to side effects like anemia. If this peptide naturally avoids that half, it could offer blood-pressure lowering with a narrower set of risks, which would matter for long-term use or for patients sensitive to current medications.

The hypothesis
EGPKLVAS selectively inhibits the C-terminal domain of somatic ACE over the N-terminal domain, because its lysine at position 4 creates an electrostatic mismatch with the positively charged residues that line the entrance to the ACE N-domain channel.
Why it’s plausible
Somatic ACE has two catalytic domains (N and C) with different substrate and inhibitor selectivities, driven partly by electrostatic properties of the substrate-binding channel entrance. The N-domain channel entrance contains positively charged residues that disfavor cationic peptides, whereas the C-domain is more tolerant of mixed-charge substrates. EGPKLVAS carries Lys at position 4, which at physiological pH is positively charged; combined with the N-terminal Glu providing partial negative charge compensation, the net charge distribution may favor C-domain engagement. This selectivity matters because N-domain inhibition is linked to ACE's role in hematopoietic stem cell biology.
Why it matters
Domain-selective ACE inhibition can separate antihypertensive from hematopoietic effects; characterizing EGPKLVAS domain selectivity would clarify its therapeutic safety window compared to non-selective ACE inhibitor drugs.
Plausibility.38
Novelty.38
Impact.50
Basis · grounding1 paper · 1 computed/note
[1]
sequenceLys at position 4 introduces a positive charge; Glu at position 1 introduces a negative charge, creating a distinctive electrostatic profile
[2]
paper
Notes ethnic differences and cis/trans conformational effects on antihypertensive peptide activity, pointing to structural selectivity as a key variable
doi: 10.1021/acs.jafc.8b02603
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.8366782069206238 boltz-2
ranking score 0.8838370442390442 boltz-2
structural qualityopenfold3
metricvaluenote
gpde0.697global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Glu-Gly-Pro-Lys-Leu-Val-Ala-Ser
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 (EGPKLVAS) (pep-04741, v1). PeptideModel. https://peptidemodel.com/card/pep-04741
@peptide{pep04741,
  sequence = {EGPKLVAS},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
references 3 papers
discussion no comments
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