pe
pep-04956 v1 CC-BY-SA-4.0

Blood-pressure-lowering peptide (FCVLRP)

A small natural peptide that blocks ACE, the enzyme that raises blood pressure, helping to lower blood pressure; studied as a potential treatment, not yet an approved drug.

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
ipTM0.636
pTM0.652
avg pLDDT86.8
ranking score0.821
STRUCTURE · PEP-04956 × ACE
ranking0.821
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence6 aa
156
FCVLRP
Hypotheses6 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

What if the active ingredient only becomes active after your gut breaks down the original compound?

If the tiny fragment RP is doing most of the blood-pressure-lowering work, researchers could skip stabilizing the whole peptide and focus on delivering RP directly, which could lead to smaller, cheaper, more effective doses. This matters for anyone developing food-based or low-cost treatments for hypertension.

The hypothesis
The antihypertensive activity of FCVLRP in vivo is mediated primarily by its gastrointestinally released dipeptide RP rather than by intact FCVLRP, because RP has an IC50 of approximately 0.39 uM at ACE, roughly 30-fold lower than the parent peptide, and RP is the stable end-product of digestive enzyme cleavage.
Why it’s plausible
The source paper (10.1002/psc.789) documents that digestive cleavage of FCVLRP generates RP as the dominant active fragment, and that most other fragment-peptides retain inhibitory activity. Because FCVLRP is a food-derived hexapeptide administered orally, it is almost certainly hydrolyzed before systemic absorption. The intact peptide therefore functions as a prodrug delivering RP to the gut lumen, where RP inhibits luminal ACE or is absorbed intact given its size.
Why it matters
If RP is the true effector, development efforts should focus on RP bioavailability and stability rather than on stabilizing the full hexapeptide, which would reshape the entire formulation and engineering strategy.
Plausibility.64
Novelty.47
Impact.82
Basis · grounding2 papers
[1]
paper
RP dipeptide IC50 = 0.39 uM, approximately 30x lower than parent FCVLRP; FC and FCVL fragments lost activity on cleavage, consistent with RP being the active species after digestion
doi: 10.1002/psc.789
[2]
paper
ACE inhibitory peptides must reach the cardiovascular system in active form to lower blood pressure, implying the relevant species may be a digest fragment
doi: 10.1079/bjn20041189
openupdated 2026-06-05

Can a blood pressure treatment avoid the side effects that come from disabling a protective enzyme your heart needs?

If FCVLRP turns out to be selective, it could lower blood pressure without suppressing the body's own counter-regulatory system, which some conventional ACE inhibitors interfere with. For patients and formulators, that could mean a cleaner safety profile compared to existing drugs.

The hypothesis
FCVLRP inhibits ACE1 but not ACE2, because its C-terminal proline confers selectivity for ACE1 (which disfavors C-terminal basic or proline residues in substrate) and because ACE2 has a distinct active-site architecture that is not compatible with proline-ended inhibitors.
Why it’s plausible
ACE1 and ACE2 are both zinc carboxypeptidases but have different substrate specificities. ACE1 cleaves dipeptides from C-termini and is strongly inhibited by peptides ending in proline. ACE2 is a monocarboxypeptidase with a distinct active site that disfavors proline at P1. If FCVLRP is selective for ACE1, it would avoid the adverse effect of reducing ACE2 activity, which is cardioprotective and involved in the renin-angiotensin counter-regulatory axis.
Why it matters
ACE1-selective inhibition without ACE2 suppression could confer cardiovascular benefit while preserving the angiotensin 1-7/Mas receptor axis, giving FCVLRP or its analogs a safety advantage over non-selective ACE inhibitors.
Plausibility.70
Novelty.35
Impact.58
Basis · grounding1 paper · 1 computed/note
[1]
sequenceC-terminal residue is proline (P), a feature associated with ACE1 selectivity in dipeptide inhibitors
[2]
paper
Some antihypertensive peptide drugs cause side effects including dry cough and edema, side effects linked to ACE1 inhibition and bradykinin accumulation; ACE2-sparing compounds may avoid these
doi: 10.1038/s41392-024-02107-5
openupdated 2026-06-05

Is there a naturally derived peptide that works better than the ones already used in functional foods for blood pressure?

If animal studies confirm the potency suggested by lab tests, FCVLRP or its fragment could become a competitive ingredient in functional foods or supplements aimed at mild hypertension, potentially requiring smaller amounts than the peptides currently used in products like fermented milk drinks.

The hypothesis
FCVLRP or its RP fragment is effective at lowering blood pressure in spontaneously hypertensive rats after oral administration at doses below 50 mg/kg, comparable to benchmark food-derived ACE inhibitor peptides VPP and IPP.
Why it’s plausible
VPP and IPP are the most clinically validated food-derived ACE inhibitor peptides with IC50 values in the low micromolar range and documented in vivo efficacy in SHR models. RP has an IC50 of 0.39 uM, considerably lower than VPP (IC50 approximately 9 uM) and IPP (IC50 approximately 5 uM). If oral bioavailability is comparable, RP should require lower doses to achieve equivalent blood-pressure reduction. Axis hits confirm that low-molecular-weight peptides can retain bioactivity through gastrointestinal digestion.
Why it matters
Demonstrating in vivo potency at low doses would establish FCVLRP as a competitive candidate for functional food or nutraceutical development targeting hypertension, directly competing with commercially used tripeptides from fermented milk.
Plausibility.52
Novelty.40
Impact.73
Basis · grounding2 papers · 1 computed/note
[1]
sourceVPP and IPP have shown significant blood pressure reductions in clinical hypertension trials; comparison benchmark for food-derived ACE inhibitor peptides
[2]
paper
RP IC50 = 0.39 uM, approximately the lowest reported for an ACE inhibitory peptide; fragment peptides expected to have in vivo effect on hypertension
doi: 10.1002/psc.789
[3]
paper
Maximum decrease in systolic blood pressure in SHR upon oral administration reported at 100 mg/kg for benchmark peptides, providing a comparison threshold
doi: 10.1016/j.foodchem.2017.02.039
openupdated 2026-06-05

If a natural peptide degrades too quickly to work well as a medicine, can a minor chemical tweak fix that without killing the effect?

If this modification holds up in testing, it could turn a fragile natural compound into a stable drug candidate with a longer shelf life and better absorption, which is a critical step in moving any peptide from a research finding toward a real product for people managing high blood pressure.

The hypothesis
Substituting the cysteine at position 2 of FCVLRP with a D-cysteine or a thioether-locked analog will increase proteolytic stability without abolishing ACE inhibitory activity, because the adjacent bulky phenylalanine at position 1 already provides partial steric shielding.
Why it’s plausible
The free thiol of Cys2 creates chemical instability through oxidation and disulfide scrambling. D-amino acid substitution is established to resist endopeptidase recognition. Because F at position 1 is bulky and aromatic, it provides some N-terminal shielding. A D-Cys2 variant would maintain the thiol for potential zinc coordination while resisting aminopeptidase cleavage from the N-terminus. The source paper shows that digestive fragments retain activity, suggesting the C-terminal RP motif is the dominant pharmacophore and N-terminal modifications may be tolerated.
Why it matters
A stabilized FCVLRP analog could extend plasma half-life and improve oral bioavailability, converting a rapidly degraded natural peptide into a druggable antihypertensive lead with improved pharmacokinetics.
Plausibility.56
Novelty.40
Impact.58
Basis · grounding2 papers · 1 computed/note
[1]
paper
D-amino acid substitution improves peptide stability in serum and inhibits enzymatic recognition by endogenous proteases; established rationale for stability engineering
doi: 10.1248/cpb.c25-00478
[2]
paper
FC and FCVL fragments lost ACE inhibitory activity upon cleavage, indicating N-terminal residues contribute to full-length potency but the C-terminal RP is the dominant active unit, suggesting N-terminal modification space
doi: 10.1002/psc.789
[3]
sequenceCys at position 2 is chemically reactive; F at position 1 provides adjacent steric bulk
openupdated 2026-06-05

Could a peptide from food hit the same two targets as a major heart failure drug, but at a fraction of the cost?

The approved drug Entresto works by blocking both ACE and neprilysin together, a combination shown to reduce deaths in heart failure. If FCVLRP turns out to share that dual action, it could open a path to a much cheaper, food-derived approach to mild hypertension or early heart failure, though this remains entirely unproven and would need extensive testing.

The hypothesis
FCVLRP inhibits neprilysin (neutral endopeptidase, NEP) in addition to ACE, because the leucine-arginine-proline C-terminal tripeptide matches the hydrophobic P1 preference of neprilysin and dual ACE/NEP inhibition is a known pharmacological synergy exploited in approved drugs such as sacubitril-valsartan.
Why it’s plausible
Neprilysin cleaves natriuretic peptides, bradykinin, and angiotensin I at hydrophobic residues. Peptide inhibitors that present hydrophobic side chains flanking the scissile bond can act as competitive substrates or inhibitors. FCVLRP contains a leucine-valine hydrophobic core and a C-terminal proline that may fit the NEP S1 subsite. Some short food-derived peptides have been shown to have dual ACE/NEP inhibitory activity. If FCVLRP inhibits NEP, it could potentiate ANP/BNP levels and provide additive blood pressure reduction beyond ACE inhibition alone.
Why it matters
Dual ACE/NEP inhibition is the mechanism of the breakthrough heart failure drug entresto; a food-derived dual inhibitor would open a nutraceutical or low-cost pharmaceutical route to that pharmacology for mild hypertension and early heart failure.
Plausibility.34
Novelty.68
Impact.77
Basis · grounding1 paper · 1 computed/note
[1]
sequenceVLR hydrophobic core matches neprilysin P2-P1-P1' preferences; proline at C-terminus is present in both ACE and some NEP inhibitor peptidomimetics
[2]
paper
Peptides with antihypertensive effects have been investigated across cardiovascular, endocrine, immune, and nervous systems, indicating multi-target potential of food-derived antihypertensive peptides
doi: 10.1016/j.foodchem.2012.08.080
openupdated 2026-06-05

Could you replace the inert middle of a peptide with something more durable, keeping the active ends intact?

If the valine-leucine segment is confirmed to be structural rather than active, drug designers could replace it with a non-peptide linker that resists breakdown in the gut, a standard strategy for turning peptides into orally stable drugs. That would be useful for anyone trying to develop this compound into a lasting antihypertensive treatment.

The hypothesis
The valine-leucine dipeptide segment (positions 3-4 of FCVLRP) is required for adopting a turn or bent conformation that positions the C-terminal RP unit in the ACE active site, and substitution of either residue with a charged or polar amino acid abolishes ACE inhibitory activity regardless of the C-terminal residues.
Why it’s plausible
Val and Leu are aliphatic, helix- and turn-promoting residues that in a hexapeptide context likely drive a compact fold placing the N-terminal FC and the C-terminal RP into proximity. The RP dipeptide is highly potent alone (0.39 uM), but in FCVLRP the full hexapeptide has lower potency, suggesting the central VL segment may impose a non-optimal geometry on RP within the active site. Replacing VL with polar residues would disrupt hydrophobic packing and abolish any conformational pre-organization, establishing VL as a structural spacer rather than a direct pharmacophore.
Why it matters
Mapping the minimal pharmacophoric scaffold would allow truncation and replacement of the VL spacer with a non-peptidic linker, a classical peptidomimetic strategy to improve metabolic stability while retaining ACE affinity.
Plausibility.35
Novelty.53
Impact.53
Basis · grounding2 papers · 1 computed/note
[1]
sequencePositions 3-4 are Val-Leu, consecutive aliphatic branched-chain residues that favor hydrophobic core formation in short peptides
[2]
paper
RP alone has IC50 = 0.39 uM while parent FCVLRP is less potent; FCVL fragment loses activity on cleavage, suggesting VL contributes to but does not solely determine activity in the parent context
doi: 10.1002/psc.789
[3]
paper
Structure-function of blood-pressure-lowering peptides: amino acid composition and sequence determine ACE inhibitory activity
doi: 10.1021/jf5002606
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.6362297534942627 boltz-2
ranking score 0.8214689493179321 boltz-2
3-letter notation
Phe-Cys-Val-Leu-Arg-Pro
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). Blood-pressure-lowering peptide (FCVLRP) (pep-04956, v1). PeptideModel. https://peptidemodel.com/card/pep-04956
@peptide{pep04956,
  sequence = {FCVLRP},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 3 by signal overlap
references 2 papers
[1]
Analysis of novel angiotensin‐I‐converting enzyme inhibitory peptides from protease‐hydrolyzed marine shrimp Acetes chinensis
Hai‐Lun H; Xiu‐Lan C; Cai‐Yun S; Yu‐Zhong Z; Bai‐Cheng Z Journal of Peptide Science 2006
source scaffold
[2]
Milk-derived bioactive peptides
Kashung, P. et al. Food Production, Processing and Nutrition 2025
supporting
discussion no comments
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