pe
pep-04920 v1 CC-BY-SA-4.0

Blood-pressure-lowering peptide (IPPVPP)

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

statuscomputed targetACE length6 aa refs2
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 · 2 contributors
prediction metrics boltz-2 1.0
ipTM0.698
pTM0.513
avg pLDDT87.2
ranking score0.837
STRUCTURE · PEP-04920 × ACE
ranking0.837
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence6 aa
156
IPPVPP
Hypotheses4 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

Does your gut need to break this peptide apart before it can actually lower blood pressure?

If true, swallowing IPPVPP could be a more reliable way to deliver IPP, a smaller peptide already shown in clinical trials to reduce blood pressure, because the larger version might survive digestion better before releasing its active piece. This could matter for people using food-based supplements to manage mild hypertension.

The hypothesis
The antihypertensive activity of IPPVPP in vivo is primarily exerted by its proteolytic fragment IPP (Ile-Pro-Pro) generated during gastrointestinal digestion, and the full hexapeptide functions as a prodrug that delivers the clinically validated dipeptide/tripeptide ACE inhibitors IPP or VPP.
Why it’s plausible
IPP and VPP are the best-characterized food-derived ACE inhibitors with clinical trial evidence. IPPVPP contains the IPP sequence at its N-terminus (residues 1-3: Ile-Pro-Pro) and a VPP-like motif (Val-Pro-Pro at residues 4-6 minus the N-terminal Ile). Gastrointestinal proteases may cleave the central Val-Pro bond, liberating IPP. The bioavailability axis hits note that low-molecular-weight peptide bioactivity can be retained during gastrointestinal digestion. This makes IPPVPP functionally analogous to a prodrug form that is more stable at the mucosal surface than the tripeptide alone.
Why it matters
If IPPVPP is a prodrug for IPP, its formulation advantage over direct IPP supplementation would be greater resistance to aminopeptidase N cleavage at the N-terminal Ile because the hexapeptide buries that residue within a proline-capped structure. This would explain better in vivo activity relative to in vitro IC50, which is a recognized paradox in food antihypertensive peptide literature.
Plausibility.79
Novelty.53
Impact.72
Basis · grounding2 papers · 2 computed/notes
[1]
sequenceIPPVPP contains IPP at positions 1-3; VPP-like motif (VAPP equivalent) at positions 4-6
[2]
sourceVPP and IPP have shown significant BP reductions in clinical trials
[3]
paper
Food-derived peptides with weaker in vitro ACE IC50 than drugs still lower blood pressure in SHR after oral administration
doi: 10.1271/bbb.59.425
[4]
paper
ACE inhibitory peptides must reach the cardiovascular system in active form; transit form may differ from the active fragment
doi: 10.1079/bjn20041189
openupdated 2026-06-05

Could a single chemical swap stop the body from destroying this peptide too fast to do any good?

Peptides taken by mouth are often chewed up by digestive enzymes before they can act. If flipping just one building block at the start of the chain blocks that breakdown, IPPVPP could stay active long enough to actually lower blood pressure, which would be an important step toward turning it into a practical supplement or drug candidate.

The hypothesis
Replacing the N-terminal isoleucine of IPPVPP with a D-isoleucine residue (D-Ile-PPVPP) will extend its plasma half-life at least 3-fold by blocking aminopeptidase N cleavage at the N-terminus while preserving ACE inhibitory activity, because the internal proline residues already constrain backbone geometry independent of N-terminal stereochemistry.
Why it’s plausible
Aminopeptidase N cleaves L-amino acid N-termini; D-substitution at position 1 is a classic strategy to block this without disrupting the rest of the peptide. In IPPVPP, the ACE-binding pharmacophore is anchored in the C-terminal region (the PP motif). The N-terminal Ile contributes to binding affinity but is not the primary pharmacophore. The proteolytic stability axis hits note that D-amino acid substitution is a well-established approach to serum stability without a requirement for direct experimental confirmation in this peptide. The proline residues at positions 2, 5, and 6 would maintain the backbone geometry after N-terminal D-substitution.
Why it matters
Oral bioavailability is the central barrier for IPPVPP clinical translation (highlighted in both the oral-bioavailability and half-life axis hits). A single D-amino acid substitution is the lowest-complexity engineering intervention; confirming it preserves activity would immediately yield a candidate with improved pharmacokinetic profile suitable for nutraceutical or drug development.
Plausibility.57
Novelty.38
Impact.57
Basis · grounding1 paper · 2 computed/notes
[1]
sourceD-amino acid substitution at the N-terminus improves peptide serum stability and inhibits aminopeptidase recognition, per established literature cited
[2]
paper
Oral administration of peptide drugs requires strategies to overcome gastrointestinal degradation
doi: 10.1038/s41392-024-02107-5
[3]
sequenceIle is at position 1 (the aminopeptidase-N cleavage site); all three prolines are internal/C-terminal and would not be affected by N-terminal D-substitution
openupdated 2026-06-05

Does this peptide work differently from standard blood pressure drugs, and could that make it safer?

Common ACE-inhibitor drugs latch onto the zinc atom inside the enzyme, which sometimes causes side effects like a persistent cough or kidney stress. If IPPVPP works by simply fitting into the enzyme's slot instead, it might reduce blood pressure with fewer of those side effects. This would help explain why it appears safer in early data, though direct clinical confirmation is still needed.

The hypothesis
IPPVPP inhibits ACE (angiotensin-converting enzyme, ACE1/CD143) as a competitive substrate-mimic by occupying the S1' and S2' subsites via its C-terminal Pro-Pro dipeptide, rather than chelating the catalytic zinc through a thiol or carboxylate warhead.
Why it’s plausible
The sequence IPPVPP terminates in a -Pro-Pro (PP) motif. Crystallographic studies of ACE with food-derived inhibitors show that C-terminal proline occupies the S2' subsite and resists carboxypeptidase cleavage, while a second proline at the penultimate position further shields the scissile bond. IPPVPP lacks a zinc-coordinating group common to drug ACE inhibitors (thiol, carboxylate), yet is tagged as an ACE inhibitor, implying a purely steric/competitive mode. The null target field and the structure prediction (no annotated docking partner) are consistent with this mechanism being inferred rather than experimentally confirmed at atomic resolution.
Why it matters
Establishing competitive substrate-mimicry as the mode of action distinguishes IPPVPP from drug-like ACE inhibitors and explains why its in vitro IC50 may be weaker than captopril while still lowering blood pressure in vivo: a weaker but safer binder with no zinc chelation side-effects (cough, renal impairment) noted in the immunogenicity-safety axis hits.
Plausibility.73
Novelty.20
Impact.47
Basis · grounding2 papers · 2 computed/notes
[1]
sequenceC-terminal PP dipeptide in IPPVPP; absence of zinc-coordinating side chains (no Cys, His, Asp at terminus)
[2]
paper
Proline presence at C-terminus is a common structural feature among potent ACE-inhibitory food peptides
doi: 10.1021/acs.jafc.8b02603
[3]
paper
Drug ACE inhibitors cause dry cough and renal impairment via zinc chelation; food-derived peptides are noted to have fewer such side effects
doi: 10.1038/s41392-024-02107-5
[4]
structureBoltz-2 structure computed; target annotation is null, consistent with no validated zinc-coordination contact
openupdated 2026-06-05

Could someone with normal blood pressure take this without worrying it will push their pressure too low?

One serious risk with prescription blood-pressure drugs is that they can cause dangerous drops in people who do not need them. If IPPVPP turns out to be too mild to override the body's own regulation when pressure is already normal, it could be used in foods or supplements without that risk, making it a safer option for the many people with borderline or diet-managed hypertension.

The hypothesis
IPPVPP selectively lowers blood pressure in hypertensive individuals but has negligible effect in normotensive subjects because its ACE inhibitory potency is insufficient to overcome the regulatory reserve of the renin-angiotensin-aldosterone system at normal plasma ACE activity levels.
Why it’s plausible
The selectivity axis hits explicitly cite that food-derived antihypertensive peptides show effects in hypertensive patients but not in normotensive subjects, attributing this to ethnic differences and dietary context. A mechanistic explanation is that plasma ACE activity is elevated in hypertension, creating a larger kinetic window for a weak competitive inhibitor (low-potency, no zinc chelation) like IPPVPP to shift the equilibrium. In normotensive individuals the compensatory RAAS response offsets modest ACE inhibition. The sequence has no charged residues (neutral peptide: I, P, P, V, P, P), which limits intrinsic potency.
Why it matters
Selectivity for the hypertensive state is a key therapeutic safety advantage over small-molecule ACE inhibitors, which cause hypotension in normotensive individuals. Establishing this selectivity mechanistically would support the use of IPPVPP-containing functional foods or nutraceuticals as adjunct therapy without the hypotension risk of drugs.
Plausibility.66
Novelty.20
Impact.47
Basis · grounding2 papers · 1 computed/note
[1]
paper
Clinical trials of food antihypertensive peptides show ethnic differences and no effect in normotensive subjects
doi: 10.1021/acs.jafc.8b02603
[2]
sequenceNo charged or aromatic residues in IPPVPP; all residues are neutral/nonpolar, consistent with low intrinsic binding affinity
[3]
paper
Maximal SBP decrease in SHR at 100 mg/kg oral dose, implying moderate potency requiring elevated baseline ACE activity
doi: 10.1016/j.foodchem.2017.02.039
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.6979984045028687 boltz-2
ranking score 0.8373614549636841 boltz-2
structural qualityopenfold3
metricvaluenote
gpde1.356global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Ile-Pro-Pro-Val-Pro-Pro
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 (IPPVPP) (pep-04920, v1). PeptideModel. https://peptidemodel.com/card/pep-04920
@peptide{pep04920,
  sequence = {IPPVPP},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 1 by signal overlap
references 2 papers
[1]
Critical Review and Perspectives on Food-Derived Antihypertensive Peptides
Miralles, B. et al. Journal of Agricultural and Food Chemistry 2018
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