pe
pep-04491 v1 CC-BY-SA-4.0

β-casein blood-pressure peptide

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

statuscomputed targetACE length50 aa refs1
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
ipTM0.316
pTM0.538
avg pLDDT76.2
ranking score0.673
STRUCTURE · PEP-04491 × ACE
ranking0.673
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence50 aa
15101520253035404550
LSSSEESTRI NKKIEKFQSE EQQQYEDELQ DKIHPFAQTQ SLVYPFPGPI
Hypotheses3 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

Is it a short tail-end fragment of this milk-derived peptide, rather than the whole molecule, that actually blocks the enzyme linked to high blood pressure?

If the real active ingredient turns out to be a small fragment, researchers could stop chasing a large, hard-to-use molecule and focus on a simple, cheap short peptide. That could speed up the development of food-based or supplement-based blood-pressure support.

The hypothesis
The 50-residue full-length peptide LSSSEESTRINKKIEKFQSEEQQQYEDELQDKIHPFAQTQSLVYPFPGPI does not inhibit ACE as an intact molecule; ACE inhibitory activity observed in the source paper is generated by proteolytic release of short C-terminal sub-fragments (specifically the YPFPGPI or PFPGPI segment) rather than by the full-length sequence.
Why it’s plausible
The Boltz-2 complex prediction yields an interface pTM of 0.317, well below the 0.5 threshold that distinguishes real from spurious interfaces, indicating the full 50-residue chain does not form a credible docked complex with ACE. ACE active-site inhibitors are typically di- or tri-peptides that occupy the S1/S2 subsites; a 50-mer would be sterically excluded from the narrow active site channel. The source paper (doi:10.1271/bbb1961.54.1101) synthesized peptide fragments, leaving open whether the intact sequence or sub-fragments were assayed. The C-terminal PFPGPI segment bears strong structural resemblance to the established ACE-inhibitory tripeptide IPP from beta-casein f(74-76) and to VPP, both of which function as short-chain ACE inhibitors by coordinating the zinc active site.
Why it matters
If confirmed, the card's primary target annotation is mechanistically misleading: the relevant pharmacophore is a short C-terminal sub-sequence, not the 50-mer. This redirects synthesis, SAR work, and IC50 measurements toward a tractable short peptide scaffold and explains why the 50-mer has never advanced past the computed stage.
Plausibility.79
Novelty.58
Impact.83
Basis · grounding1 paper · 2 computed/notes
[1]
structureBoltz-2 complex ipTM = 0.317, ranking_score = 0.673; interface confidence is too low to support a direct ACE-binding model for the full 50-mer.
[2]
sequenceC-terminal segment YPFPGPI contains the tripeptide PGP and the PF dipeptide; the PFPGPI sub-sequence is homologous to known short-chain beta-casein ACE inhibitors such as IPP and VPP.
[3]
paper
Paper title describes 'synthetic peptide fragments of various beta-caseins'; subtle sequence changes abolished activity, consistent with a short active-site pharmacophore rather than a large domain.
doi: 10.1271/bbb1961.54.1101
openupdated 2026-06-05

Is the four-unit sequence IHPF the smallest piece of this peptide that still blocks the blood-pressure-raising enzyme, with the rest of the molecule being just scaffolding?

If those four units are enough, chemists could build them easily and cheaply instead of wrestling with a large 50-unit molecule. That kind of simplification is often what moves a promising food-science finding toward an actual product people could take.

The hypothesis
The IHPF tetrapeptide (residues 35-38) within the sequence DKIHPFAQTQ is the minimal ACE-inhibitory pharmacophore of this peptide, and the flanking residues D, K, A, Q act as solubility and stability modulators that do not contribute to zinc coordination.
Why it’s plausible
His-Pro dipeptide and tripeptides ending in a hydrophobic residue (Phe, Trp, Tyr) are the best-characterized ACE inhibitory pharmacophores: they coordinate the active-site zinc via the His imidazole and occupy the S1 hydrophobic pocket with the C-terminal aromatic ring. IHPF contains exactly this arrangement: Ile at P3 (hydrophobic spacer), His at P2 (zinc ligand), Pro at P1' (conformational constraint), Phe at C-terminus (S1 anchor). Beta-casein is the parent protein and its hydrolysis products routinely yield HPF-containing ACE inhibitors. The original study (doi:10.1271/bbb1961.54.1101) noted that subtle structural changes abolish activity, pointing to a single critical pharmacophoric region rather than distributed contacts across the full sequence.
Why it matters
Identifying IHPF as the minimal pharmacophore allows truncation of the 50-mer to a tractable 4-mer for medicinal chemistry, drastically reducing synthesis cost (50-mer at the upper SPPS length limit; 4-mer trivial) and improving oral bioavailability. A confirmed IHPF minimal pharmacophore also suggests a class of His-Pro-Phe tripeptide analogs as natural ACE inhibitor scaffolds.
Plausibility.55
Novelty.48
Impact.75
Basis · grounding2 papers · 1 computed/note
[1]
sequenceIHPF at positions 35-38 (DKIHPFAQTQ context): His-Pro-Phe C-terminal tripeptide motif is the canonical ACE zinc-coordinating pharmacophore.
[2]
paper
Species orthologs with subtle sequence differences lose all ACE inhibitory activity, consistent with a single short pharmacophore rather than distributed contacts.
doi: 10.1271/bbb1961.54.1101
[3]
paper
Beta-casein fragment HLPLP retains antihypertensive activity as a pentapeptide with 5% oral bioavailability, demonstrating that short casein sub-sequences are biologically competent independently of the full parent sequence.
doi: 10.1021/acs.jafc.8b02603
openupdated 2026-06-05

Does the blood-pressure effect of this milk-derived peptide come mainly from activating the body's natural opioid receptors, the same ones involved in pain and mood, rather than from blocking the enzyme usually targeted by blood-pressure drugs?

If opioid receptors are the real driver, any product built on this peptide would need to be evaluated for very different safety concerns, including potential nervous-system effects. That matters for anyone developing a dairy-based supplement or food ingredient marketed for heart health, and for regulators deciding how to handle it.

The hypothesis
The antihypertensive activity of this beta-casein peptide in vivo is mediated through mu-opioid receptor agonism rather than ACE inhibition, with the KIEK motif (residues 13-16) acting as the opioid-active core.
Why it’s plausible
Axis hits from doi:10.1021/acs.jafc.9b03872 show that the in vivo blood pressure effect of casein hydrolysates containing similar sequences is blocked by opioid receptor antagonists, not by ACE inhibitor reversal. The peptide contains a KIEKFQ segment (residues 13-18) where the basic-hydrophobic arrangement (Lys-Ile-Glu-Lys) loosely parallels known casomorphin sequences. Beta-casomorphin-7 from the same parent protein (bovine beta-casein) uses a YPFP anchor and activates mu-opioid receptors; the YPFP motif is also present in the C-terminal YPFPGPI stretch of pep-04491, suggesting dual pharmacophore architecture. Opioid receptor activation lowers sympathetic tone and vasopressin release independently of ACE, explaining discordance between in vitro ACE IC50 and in vivo blood pressure data commonly seen for casein peptides.
Why it matters
Establishing opioid receptor involvement rather than ACE inhibition as the dominant mechanism fundamentally changes the selectivity risk profile (addiction liability, CNS effects) and the regulatory path for any nutraceutical or pharmaceutical development, and explains why in vitro ACE inhibition predicts in vivo antihypertensive activity so poorly for this class.
Plausibility.40
Novelty.53
Impact.72
Basis · grounding2 papers · 1 computed/note
[1]
paper
In vivo antihypertensive effect of alphas1-casein hydrolysate peptides was mediated by opioid receptor interaction; opioid contribution implicated across casein peptide class.
doi: 10.1021/acs.jafc.9b03872
[2]
sequenceYPFP tetrapeptide (residues 45-48) within YPFPGPI is the canonical beta-casomorphin N-terminal pharmacophore that confers mu-opioid activity.
[3]
paper
Tyr-Pro dipeptide from casein has hypotensive action via a mechanism distinct from ACE inhibition, operating with a 6-hour delay consistent with opioid receptor internalization kinetics.
doi: 10.54393/fbt.v6i1.215
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.3163970112800598 boltz-2
ranking score 0.6730070114135742 boltz-2
3-letter notation
Leu-Ser-Ser-Ser-Glu-Glu-Ser-Thr-Arg-Ile-Asn-Lys-Lys-Ile-Glu-Lys-Phe-Gln-Ser-Glu-Glu-Gln-Gln-Gln-Tyr-Glu-Asp-Glu-Leu-Gln-Asp-Lys-Ile-His-Pro-Phe-Ala-Gln-Thr-Gln-Ser-Leu-Val-Tyr-Pro-Phe-Pro-Gly-Pro-Ile
recipeboltz-2 1.0
parametervalue
modelboltz-2 1.0
weights
hardwarenvidia_nim_api
mlx version
python
random seed
msa strategycolabfold_nvidia
diffusion samples1
runtime
predicted bymlx@peptide
predicted at2026-04-25
citationbibtex
peptidemodel (2026). β-casein blood-pressure peptide (pep-04491, v1). PeptideModel. https://peptidemodel.com/card/pep-04491
@peptide{pep04491,
  sequence = {LSSSEESTRINKKIEKFQSEEQQQYEDELQDKIHPFAQTQSLVYPFPGPI},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 5 by signal overlap
references 1 papers
discussion no comments
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