pe
pep-04561 v1 CC-BY-SA-4.0

Ovalbumin blood-pressure peptide

A small protein fragment that blocks ACE, an enzyme that pushes blood pressure up; used only as a lab research tool.

statuscomputed targetACE length13 aa refs1
angiotensin-converting-enzyme-ace-inhibitors
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 2 / 5 · 2 contributors
prediction metrics boltz-2 1.0
ipTM0.784
pTM0.566
avg pLDDT89.6
ranking score0.874
STRUCTURE · PEP-04561 × ACE
ranking0.874
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence13 aa
151013
AFKDEDTEEVPFR
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 food-derived peptide lower blood pressure without disturbing the other jobs ACE does in the body?

Most ACE-inhibiting drugs hit both active sites of the enzyme, which can interfere with blood cell production. If this peptide turns out to be selective for just the blood-pressure-controlling site, it could offer a cleaner safety profile for people who need long-term hypertension management.

The hypothesis
AFKDEDTEEVPFR is selective for the C-domain active site of somatic ACE over the N-domain active site, because its C-terminal -PFR tripeptide fits the C-domain S2 subsite that strongly prefers hydrophobic residues at P2, while the N-domain prefers substrates without a bulky residue at that position.
Why it’s plausible
Somatic ACE has two catalytic domains (N and C) with distinct substrate preferences. C-domain-selective inhibitors are associated with reduced interference with N-domain-mediated processing of hemoregulatory peptides such as AcSDKP. The Phe at the penultimate position of AFKDEDTEEVPFR is a bulky aromatic group that would sterically favor C-domain binding where the S2' subsite accommodates large hydrophobic side chains more readily than the N-domain equivalent. C-domain selectivity would also avoid the N-domain-mediated degradation of the anti-fibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline.
Why it matters
Selectivity for the ACE C-domain would give this peptide a cleaner cardiovascular safety profile compared to non-selective dual-domain inhibitors, and would position it as a template for designing domain-selective food-derived peptide antihypertensives with lower incidence of hematopoietic side effects.
Plausibility.53
Novelty.48
Impact.67
Basis · grounding2 papers · 1 computed/note
[1]
sequenceThe -PFR C-terminus places aromatic Phe at the P2 position, which is a known discriminating feature for ACE C-domain vs. N-domain selectivity.
[2]
paper
Original paper characterizes ACE-inhibitory activity but does not distinguish domain selectivity; the gap suggests the domain question is open.
doi: 10.1016/j.ifset.2013.02.002
[3]
paper
Notes that casein-derived peptides with moderate IC50 values can still be effective oral antihypertensives, consistent with partial/selective inhibition being pharmacologically relevant.
doi: 10.1017/s0022029999003556
openupdated 2026-06-05

Does the three-dimensional shape of this peptide matter more than its chemical charge for blocking ACE?

If the geometry of the peptide, not just its electric charge, is what makes it effective, drug designers could build shorter or ring-shaped versions that hold the right shape permanently. That could mean stronger blood-pressure-lowering compounds without making the molecule bigger or more complex.

The hypothesis
The acidic cluster DEDTEEV forms a short alpha-helical or turn segment that positions the hydrophobic N-terminal Ala-Phe and the C-terminal Pro-Phe-Arg on opposite faces of the peptide, creating a bipartite binding surface where each face contacts a different ACE subsite, and disruption of this intramolecular organization by point mutation of Asp4 or Glu9 abolishes ACE-inhibitory activity disproportionately relative to the charge change alone.
Why it’s plausible
In a 13-residue peptide, sequence context determines the local backbone geometry. The DEDTEEV stretch is enriched in residues (Asp, Glu, Thr) that favor extended or turn conformations, while Pro at position 11 introduces rigidity. If the intervening acidic segment acts as a spacer that orients the N-terminal hydrophobic anchor and the C-terminal ACE-binding motif, then the geometry rather than charge per se is the key contributor. This is testable because scrambled charge-conservative substitutions (Asp to Glu, Glu to Asp at different positions) that maintain total charge but disrupt spacing would change activity if orientation is the mechanism, but not if net charge alone drives binding.
Why it matters
Establishing that a geometric constraint within the acidic central domain governs potency would provide a structure-activity relationship rule for designing improved analogues: truncated or cyclized variants that lock the active conformation could achieve lower IC50 without increasing peptide length or molecular weight.
Plausibility.47
Novelty.57
Impact.55
Basis · grounding2 papers · 1 computed/note
[1]
sequencePositions 4-10 (DEDTEEV) are dominated by polar/acidic residues with Pro at position 11 imposing rigidity; N-terminal Ala-Phe (positions 1-2) and C-terminal Pro-Phe-Arg (positions 11-13) are hydrophobic/basic bookends.
[2]
paper
Structure-function of blood-pressure-lowering peptides is under-studied; amino acid composition and sequence determine antihypertensive activity but mechanistic rules for acidic-cluster peptides have not been established.
doi: 10.1021/jf5002606
[3]
paper
Identifies the intact 13-mer as the ACE-inhibitory species; no truncation or alanine-scan data reported, leaving the active pharmacophore uncharacterized.
doi: 10.1016/j.ifset.2013.02.002
openupdated 2026-06-05

Could this peptide survive digestion well enough, or break into pieces that still lower blood pressure?

If the peptide acts like a prodrug that releases active fragments in the gut, it could be added to everyday foods such as yogurt or protein drinks in its natural form and do its job after digestion. That would make formulation far simpler than engineering pre-digested peptide supplements.

The hypothesis
AFKDEDTEEVPFR retains antihypertensive potency after simulated gastrointestinal digestion because the acidic central segment DEDTEEV resists pepsin and pancreatin cleavage (no preferred large hydrophobic flanking residues at pepsin cleavage sites), and the resulting shorter fragments still carry the C-terminal -PFR ACE-binding motif, making the peptide effectively a pro-drug that generates active metabolites in the gut lumen.
Why it’s plausible
Pepsin cleaves preferentially at Phe-X, Leu-X, and Tyr-X bonds; pancreatin cleaves at basic and hydrophobic sites. In AFKDEDTEEVPFR, the Phe at position 2 is adjacent to Lys (position 3), which is not a preferred pepsin acceptor, and the dominant acidic stretch lacks the hydrophobic neighbors required for rapid pancreatin action. Even if the peptide is cleaved between Phe2 and Lys3, the C-terminal fragment KDEDTEEVPFR still carries the ACE-binding Arg terminus. This stepwise degradation-to-active-fragment pattern is established for casein-derived IPP and VPP, which are too short to be further hydrolyzed. A similar stability-to-active-fragment trajectory would explain why moderate-IC50 food peptides are effective antihypertensives in vivo.
Why it matters
If AFKDEDTEEVPFR functions as a gastrointestinal pro-drug, it could be incorporated into functional foods or nutraceuticals in its intact form while relying on in-lumen proteolysis to generate the pharmacologically active fragments at the intestinal surface, simplifying formulation requirements compared to pre-digested shorter peptides.
Plausibility.45
Novelty.42
Impact.60
Basis · grounding3 papers · 1 computed/note
[1]
sequencePepsin cleavage site Phe2-Lys3 would generate KDEDTEEVPFR, which retains the C-terminal Arg; the acidic segment lacks internal hydrophobic-hydrophobic pairs favored by pancreatin.
[2]
paper
ACE-inhibitory peptides LGFPTTKTYFPHF and VVYPWT showed little change in ACE-inhibitory activity after in vitro incubation with gastrointestinal proteases, establishing precedent for GI stability of multi-residue food peptides.
doi: 10.1016/j.peptides.2006.05.025
[3]
paper
Oligopeptides must survive brush-border peptidase hydrolysis to reach the bloodstream intact; partial degradation that preserves an active C-terminal fragment is a viable alternative route.
doi: 10.1039/c6fo01411a
[4]
paper
Source paper does not report GI stability data for AFKDEDTEEVPFR; the question is explicitly unresolved.
doi: 10.1016/j.ifset.2013.02.002
openupdated 2026-06-05

Could this peptide influence two related enzymes at once, shifting the body toward its natural vasodilating hormones?

Standard blood-pressure drugs block ACE1 but leave ACE2 activity unchanged. If this peptide modulates both, it could tilt the renin-angiotensin system toward hormones that relax blood vessels rather than just cutting off the ones that tighten them. That wider action might offer a more balanced cardiovascular effect for people with hypertension.

The hypothesis
AFKDEDTEEVPFR inhibits ACE2 (angiotensin-converting enzyme 2) in addition to ACE1, because the C-terminal -PFR tripeptide presents a substrate-mimicking motif compatible with ACE2's S1/S2 subsites, meaning the peptide modulates the ACE1/ACE2 balance and thereby angiotensin-(1-7) availability.
Why it’s plausible
ACE2 cleaves the C-terminal residue of angiotensin II and processes other substrates with a preference for hydrophobic or basic C-terminal residues. The -PFR terminus of AFKDEDTEEVPFR (Pro-Phe-Arg) contains a basic Arg at P1 and a bulky Phe at P2, a pattern that overlaps with ACE2 recognition motifs. Food-derived peptides with basic C-terminal residues have been shown to interact with both ACE isoforms; dual activity would shift the renin-angiotensin axis toward the vasodilatory arm rather than merely reducing angiotensin II.
Why it matters
If confirmed, AFKDEDTEEVPFR would represent a dual ACE1/ACE2 modulator from dietary protein, with a more favorable hemodynamic profile than selective ACE1 inhibitors because ACE2-sparing preserves bradykinin and angiotensin-(1-7) signaling. This would distinguish it mechanistically from captopril-class drugs.
Plausibility.35
Novelty.58
Impact.67
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC-terminal tripeptide -PFR contains basic Arg at P1 and aromatic Phe at P2, matching ACE2 subsite preferences for hydrophobic/basic C-terminal residues.
[2]
paper
ACE also degrades bradykinin; ACE2 counter-regulates this axis; understanding which enzyme is targeted changes the pharmacological outcome.
doi: 10.1016/j.peptides.2016.05.008
[3]
paper
Peptide identified from ostrich egg white hydrolysate with ACE-inhibitory activity; specific isoform was not disambiguated in the source paper.
doi: 10.1016/j.ifset.2013.02.002
openupdated 2026-06-05

Would curling this peptide into a closed loop make it stick to its target better and survive longer in the body?

Linear peptides flop around in solution, which costs energy when they bind to a target. Forming a ring could freeze this peptide in the shape it needs to work, potentially boosting potency severalfold and resisting digestive breakdown. If that holds, it could move from a mild food-derived compound to a genuine oral drug candidate for hypertension.

The hypothesis
Cyclization of AFKDEDTEEVPFR via a lactam bridge between the Lys3 side-chain amine and the C-terminal carboxylate of Arg13 yields a conformationally constrained analogue with at least 5-fold improved ACE-inhibitory potency compared to the linear peptide, because cyclization locks the -PFR terminus in the binding-competent orientation that the linear peptide only transiently samples in solution.
Why it’s plausible
Linear 13-residue peptides have high conformational entropy in solution; the entropic cost of binding to a structured active site reduces affinity. A head-to-tail or side-chain-to-terminus lactam cyclization in AFKDEDTEEVPFR would be feasible because Lys3 (epsilon-amine) and the C-terminal carboxylate of Arg13 are available for amide bond formation without disrupting the acidic central segment or the C-terminal guanidinium needed for ACE binding. Cyclic food-peptide analogues with improved ACE IC50 have been reported in the broader antihypertensive peptide literature, and the peptide length (13 aa) is within the range where macrolactamization by solid-phase methods is practical.
Why it matters
A cyclic analogue with improved potency and likely improved proteolytic stability would transform AFKDEDTEEVPFR from a moderate-activity food peptide into a lead compound for oral antihypertensive drug development, bridging the gap between nutraceutical and pharmaceutical applications.
Plausibility.42
Novelty.47
Impact.60
Basis · grounding2 papers · 1 computed/note
[1]
sequenceLys3 epsilon-amine and Arg13 C-terminal carboxylate are positioned 10 residues apart; macrolactamization across this distance in a 13-mer is geometrically feasible and would preserve the ACE-binding PFR terminus with a constrained geometry.
[2]
paper
Conformational constraint via chemical modification (e.g., D-amino acid substitution, cyclization) is a well-established strategy to improve potency and proteolytic stability of peptide drugs.
doi: 10.1248/cpb.c25-00478
[3]
paper
Structure-function of antihypertensive peptides is understudied; cyclization as a potency-enhancing modification for food-derived ACE inhibitors has not been specifically explored for ovalbumin fragments.
doi: 10.1021/jf5002606
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.7840153574943542 boltz-2
ranking score 0.8736600279808044 boltz-2
structural qualityopenfold3
metricvaluenote
gpde1.051global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Ala-Phe-Lys-Asp-Glu-Asp-Thr-Glu-Glu-Val-Pro-Phe-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). Ovalbumin blood-pressure peptide (pep-04561, v1). PeptideModel. https://peptidemodel.com/card/pep-04561
@peptide{pep04561,
  sequence = {AFKDEDTEEVPFR},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 1 by signal overlap
references 1 papers
discussion no comments
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