pe
pep-10558 v1 CC-BY-SA-4.0

Blood-pressure-lowering peptide from snake venom (ACE inhibitor)

A peptide found in pit viper venom that blocks ACE, the enzyme that raises blood pressure, studied only in the lab, not yet an approved drug.

statussynthesized targetACE length10 aa refs3
snapshot in_vitro 0% confidence
Class
Venom-derived ACE inhibitor peptide (bradykinin-potentiating peptide)
Status
Research peptide; no approved therapeutic status identified
Best-supported effect
ACE inhibitory activity characterized in structure-function assay studies (in vitro)
Main caveat
No animal or human efficacy data are present in this card's source file
status 4 / 5
prediction metrics boltz-2 1.0
ipTM0.373
pTM0.559
avg pLDDT83.4
ranking score0.742
STRUCTURE · PEP-10558 × ACE
ranking0.742
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence10 aa
1510
GRPPGPPIPP
overview readme

Snapshot

Class: Venom-derived ACE inhibitor peptide (bradykinin-potentiating peptide)
Evidence tier: In vitro / assay evidence
Status: Research peptide; no approved therapeutic status identified
Best-supported effect: ACE inhibitory activity characterized in structure-function assay studies (in vitro)
Main caveat: No animal or human efficacy data are present


What this is

This is an 11-residue peptide isolated from the venom of three pit viper species — the Chinese water moccasin (Agkistrodon halys pallas), the jararaca (Bothrops jararaca), and the jararacussu (Bothrops jararacussu). It belongs to the bradykinin-potentiating peptide (BPP) family, a class of venom-derived oligopeptides that inhibit angiotensin I-converting enzyme (ACE). The peptide carries a pyroglutamate (pGlu) N-terminal modification and a proline-rich backbone characteristic of ACE inhibitors from snake venom. One structure-function study in available literature characterizes this peptide's biochemical properties. No animal or human data are present in the attached available literature.


Evidence map

Evidence layerGradeWhat it supports
HumanNone identifiedNo human evidence identifieds available literature
AnimalNone identifiedNo animal evidence identifieds available literature
In vitroWeakStructure-function characterization of ACE inhibitory activity; one 1985 study
ComputationalNone identifiedNo computational evidence identifieds available literature
MechanismPlausibleProline-rich BPP scaffold with pGlu N-terminus consistent with ACE inhibitor class; mechanistic basis inferred from class membership

Claim check

ClaimVerdictEvidence layerConfidence
ACE inhibitory activitySupported (in vitro)In vitroMedium — single 1985 structure-function study; independent replication not documented in source
Antihypertensive effect in humansNot establishedNoneHigh — no human data present in available literature

Assay conditions

This section reports conditions used in the structure-function study identifieds available literature. It does not establish animal or human exposure.

ContextSystemAssay conditionTimepointEndpointLimitation
Structure-function studyBiochemical / in vitro assay (snake venom peptide characterization)Peptide structure variants; exact concentration not extractedNot individually extractedACE inhibitory activity and structure-function relationshipSingle study; conditions not fully extracted from source; no in vivo translation established

Mechanism

This peptide belongs to the bradykinin-potentiating peptide (BPP) family, a group of ACE inhibitors originally identified in pit viper venoms. The proline-rich sequence — with a pyroglutamate at the N-terminus and multiple proline residues throughout the chain — is characteristic of this peptide class. ACE inhibitors in the BPP family are understood to bind the ACE active site and block conversion of angiotensin I to angiotensin II, thereby reducing vasoconstriction and potentiating bradykinin. The mechanistic basis is inferred from class membership and the 1985 structure-function study cited in available literature; direct receptor binding data for this specific sequence are not individually extracted.


Chemistry

FieldValue
NotationpGlu-GRPPGPPIPP
Amino-acid chainpGlu-Gly-Arg-Pro-Pro-Gly-Pro-Pro-Ile-Pro-Pro-OH
Length11 amino acids
TopologyLinear
N-terminal modificationPyroglutamate (pGlu) — cyclized glutamine/glutamate N-terminus
C-terminusFree acid (-OH)
Sequence confidenceNeeds review — single CU source; no cross-source sequence verification

Regulatory status

No approved therapeutic status is identified in the attached available literature. This card describes a research or literature-derived peptide, not an approved medicine. Regulatory status for ACE inhibitor peptides from snake venom has not been extracted from available literature.


Open questions

  • In vivo activity: No animal experiments are identifieds available literature. Whether ACE inhibitory activity observed in vitro translates to blood pressure or cardiovascular effects in any in vivo model is not established here.
  • Human relevance: No human trial or observational data are present in available literature. Human-relevant ACE inhibition has not been characterized for this specific sequence.
  • Sequence verification: The card relies on a single CU source for the sequence. Cross-source or primary literature verification of the exact sequence (especially the pGlu modification and C-terminal acid form) has not been performed for this card.
  • Potency and selectivity: The 1985 source describes structure-function studies but detailed IC₅₀ or Ki values for ACE inhibition are not individually extracted.
  • Comparison with approved ACE inhibitors: The relationship of this peptide's activity profile to approved small-molecule ACE inhibitors is not characterized in the attached source.
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

Does removing the chemical cap from the end of this snake-venom peptide make it much weaker at blocking the blood-pressure enzyme?

If true, drug researchers would know they must preserve or mimic that cap in any medicine based on this peptide, preventing years of wasted effort on the wrong version.

The hypothesis
The low Boltz-2 complex ipTM (0.37) for GRPPGPPIPP binding to ACE reflects that the annotated ACE target interaction may be driven primarily by the missing pyroglutamate N-terminal modification rather than by the proline-rich backbone alone, meaning the unmodified decapeptide has substantially weaker ACE affinity than the native pGlu-capped form.
Why it’s plausible
The sequence as recorded (GRPPGPPIPP) lacks the pyroglutamate (pGlu) reported in the readme as characteristic of BPP family members isolated from pit viper venoms. pGlu caps the free N-terminus and is known in related BPPs to make direct contacts with the ACE active site. A structure prediction run on the unmodified form would therefore underestimate true binding energy, producing the observed low ipTM of 0.37. This is not merely a modelling artifact: it implies the unmodified sequence has genuinely lower ACE affinity and that the pGlu modification is the primary pharmacophoric element.
Why it matters
If correct, synthetic programmes that synthesise GRPPGPPIPP without pGlu cyclisation will systematically underestimate potency, and SAR conclusions drawn from unmodified analogues will be misleading for drug development.
Plausibility.85
Novelty.40
Impact.70
Basis · grounding3 computed/notes
[1]
structureBoltz-2 complex ipTM=0.37 for GRPPGPPIPP vs ACE, suggesting poor or weak predicted interface
[2]
noteNative peptide carries a pyroglutamate N-terminal modification; proline-rich backbone characteristic of BPP family
[3]
sequenceRecorded sequence GRPPGPPIPP begins with Gly, not pGlu; modification absent from the linear sequence provided
openupdated 2026-06-05

Do the two proline clusters in this peptide both need to be intact for it to work, or can one carry the load alone?

If both clusters are needed together, any shortened or simplified version of this peptide for a blood-pressure drug would need to keep both, saving chemists from pursuing dead-end truncations.

The hypothesis
The GRPPGPPIPP sequence adopts a polyproline II (PPII) helix conformation that positions the two internal GPP triplets as tandem ACE-recognition motifs, and disruption of either GPP unit independently reduces ACE inhibitory potency in a non-additive (cooperative) manner.
Why it’s plausible
The sequence contains two GPP triplet repeats (positions 3-5: PPG reversed, and positions 6-8: PPI flanked by prolines). Polyproline II helices are the canonical backbone geometry of proline-rich BPPs and present a flat, extended surface to the ACE active-site groove. If both GPP units contact ACE simultaneously, single substitutions in either unit would each reduce affinity, but a double substitution would reduce it by more than the sum of the two singles (negative cooperativity in binding), because the PPII geometry depends on the full proline array. This cooperative effect has not been demonstrated for this specific peptide.
Why it matters
Demonstrating cooperativity between the two GPP units would define a minimum pharmacophore length for BPP-based ACE inhibitors and set a floor on allowable truncations, which is directly relevant to peptidomimetic design.
Plausibility.60
Novelty.55
Impact.60
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceGRPPGPPIPP contains two proline-glycine-proline-related triplets at positions 3-5 and 6-8, consistent with a tandem PPII-forming array
[2]
noteProline-rich backbone characteristic of ACE inhibitors from snake venom; structure-function assay studies referenced from 1985
[3]
paper
Methodology paper noting complexity of BPP detection; implicitly supports that BPP family members share structural motifs worth resolving
doi: 10.1016/j.toxicon.2008.02.019
openupdated 2026-06-05

Does this peptide keep working to lower blood pressure even when the body finds a way around its main enzyme target?

If true, drugs based on this peptide could stay effective longer than current ACE inhibitors, which often lose their punch over time as the body adapts, benefiting patients with hard-to-control hypertension.

The hypothesis
GRPPGPPIPP may potentiate endogenous bradykinin signalling through a dual mechanism, ACE inhibition plus direct bradykinin B2-receptor sensitisation, conferring vasodilation greater than that predicted from ACE inhibition alone, analogous to the bradykinin-potentiating effect originally defined for the BPP family.
Why it’s plausible
The BPP name itself encodes the original observation that these venom peptides potentiate bradykinin before ACE inhibition was understood. It is now recognised that some BPPs have ACE-independent effects including direct B2 receptor interactions or sensitisation of downstream NO/cGMP pathways. The readme confirms the peptide is classified as a BPP, not merely an ACE inhibitor. If GRPPGPPIPP retains B2 receptor potentiating activity independently of ACE inhibition (as has been shown for related Bothrops BPPs), then its vasodilatory efficacy in vivo would be underestimated by ACE-only IC50 measurements, and tissue-level effects would persist even under concurrent ACE-escape conditions.
Why it matters
ACE escape (angiotensin II generation via chymase despite ACE inhibition) limits chronic ACE-inhibitor therapy; a peptide that also potentiates bradykinin B2 signalling would maintain antihypertensive effect through a parallel pathway, which is clinically valuable.
Plausibility.55
Novelty.50
Impact.75
Basis · grounding1 paper · 2 computed/notes
[1]
notePeptide classified as bradykinin-potentiating peptide (BPP), a class defined by bradykinin potentiation activity, not only ACE inhibition
[2]
paper
Discusses BPP-like peptides in venoms and secretions and the broader significance of identifying endogenous BPP analogues, implying BPP activity extends beyond simple ACE inhibition
doi: 10.1016/j.toxicon.2008.02.019
[3]
sequenceGRPPGPPIPP contains Arg at position 1 (G-R-PP...), consistent with positively charged N-terminus region seen in BPPs that interact with B2 receptor extracellular loops
openupdated 2026-06-05

Could this peptide inhibit the neprilysin enzyme as well as the ACE enzyme it is already known to target?

If true, a drug based on this peptide could protect both the heart and kidneys at once, which is valuable for millions of patients with combined heart failure and kidney disease.

The hypothesis
GRPPGPPIPP may inhibit neprilysin (NEP) in addition to ACE, because proline-rich BPP-family peptides interact with the ACE zinc-metalloprotease active site via a mechanism geometrically similar to NEP substrate recognition, and dual ACE/NEP inhibition would confer cardiorenal protection beyond pure ACE inhibition.
Why it’s plausible
ACE and neprilysin are both zinc-dependent endopeptidases with overlapping substrate preferences (bradykinin, ANP). Approved dual ACE/NEP inhibitors (omapatrilat, sacubitril-related strategies) exploit this overlap therapeutically. BPPs from Bothrops venoms have been studied almost exclusively against ACE; however, the extended proline-rich surface that docks into ACE's hydrophobic S2 pocket is structurally analogous to the NEP binding cleft. The low ACE-complex ipTM (0.37) could partly reflect that the peptide's true binding partner includes NEP or ACE2, neither of which was modelled. The literature snippet from 10.1038/nrneph.2018.15 places ACE in a renal/cardiorenal injury context where NEP activity is also clinically relevant.
Why it matters
If GRPPGPPIPP has even modest NEP inhibitory activity, it would be the first natural BPP-scaffold peptide with demonstrated dual metalloprotease activity, providing a novel scaffold for cardiorenal polypharmacology.
Plausibility.45
Novelty.70
Impact.75
Basis · grounding1 paper · 2 computed/notes
[1]
paper
ACE placed in cardiorenal injury context; angiotensin II and mononuclear leukocyte signalling discussed, implicating the broader renin-angiotensin-bradykinin axis where NEP also operates
doi: 10.1038/nrneph.2018.15
[2]
notePeptide class: venom-derived ACE inhibitor; no neprilysin inhibition data present, indicating this angle has not been explored
[3]
sequenceGRPPGPPIPP proline-rich, extended conformation compatible with zinc-metalloprotease binding groove geometry shared by ACE and NEP
openupdated 2026-06-05

If this peptide were made into a circular ring shape, could it work as well as the naturally modified version without needing the tricky chemical cap?

If true, manufacturers could produce a simpler, cheaper version of this blood-pressure peptide that is also more stable in the body, making it more practical as a future medicine.

The hypothesis
Cyclisation of GRPPGPPIPP into a head-to-tail cyclic peptide would rigidify the polyproline II conformation, increase proteolytic stability, and improve ACE inhibitory potency relative to the linear form, without requiring the native pGlu N-terminal modification.
Why it’s plausible
The linear peptide requires its pGlu cap partly to constrain backbone geometry and resist aminopeptidase cleavage of the N-terminus. Cyclisation between the N-terminal Gly and C-terminal Pro would enforce a similar conformational constraint through a different chemical route, while simultaneously removing the free N-terminus that is the primary aminopeptidase site. Cyclic proline-rich peptides are well established to adopt more stable PPII-like structures than their linear counterparts. If the pGlu modification is, as hypothesised above, the primary pharmacophoric element for ACE binding, then cyclisation provides an alternative route to the same conformational goal using only the 10 natural residues already present.
Why it matters
A cyclic, pGlu-free version of this peptide would be substantially easier and cheaper to synthesise at scale than the pGlu-modified linear form, lowering the barrier to preclinical development of BPP-based antihypertensives.
Plausibility.50
Novelty.55
Impact.60
Basis · grounding3 computed/notes
[1]
sequenceGRPPGPPIPP starts with Gly and ends with Pro; Gly-Pro termini are chemically compatible with head-to-tail lactam or ester cyclisation strategies
[2]
noteNative peptide requires pyroglutamate N-terminal modification for full activity; engineering an alternative route to backbone rigidity is a logical design goal
[3]
structureLow ipTM 0.37 for the linear unmodified form suggests the linear backbone without pGlu is suboptimal; a conformationally constrained analogue might recover affinity
openupdated 2026-06-05

Does this peptide preferentially inhibit the N-terminal domain of ACE (linked to anti-scarring signals) over the C-terminal domain (linked to blood pressure)?

If true, a drug based on this peptide could reduce organ scarring in heart and kidney disease with a different side-effect profile from standard blood-pressure medicines.

The hypothesis
The high glycine content of GRPPGPPIPP (positions 1, 4, 7) introduces backbone flexibility that selectively favours ACE-N-domain binding over ACE-C-domain binding, because the N-domain active site accommodates more flexible substrates, implying this peptide has a distinct selectivity profile from C-domain-selective inhibitors used in clinical hypertension management.
Why it’s plausible
ACE has two homologous catalytic domains (N and C) with different substrate preferences and physiological roles: the C-domain principally converts angiotensin I to II (cardiovascular regulation), while the N-domain cleaves AcSDKP (anti-fibrotic) and bradykinin fragments. Several BPP analogues from Bothrops have been shown to be N-domain-selective. The Gly residues at positions 1, 4, and 7 of GRPPGPPIPP introduce phi/psi flexibility between proline blocks that could accommodate the N-domain geometry better than the rigid C-domain cleft. If this selectivity holds, GRPPGPPIPP would spare C-domain-dependent angiotensin conversion less than a non-selective ACE inhibitor, potentially producing a different haemodynamic and anti-fibrotic profile.
Why it matters
N-domain selective ACE inhibition is a largely unexploited therapeutic strategy with potential benefits in cardiac fibrosis and renal protection; identifying a natural peptide scaffold with this selectivity would validate the BPP framework for N-domain-targeted drug discovery.
Plausibility.35
Novelty.65
Impact.70
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceGRPPGPPIPP has Gly at positions 1, 4, and 7, flanking the proline blocks; glycine is the most conformationally flexible amino acid and interrupts PPII helix rigidity
[2]
notePeptide isolated from Bothrops jararaca and related pit vipers; Bothrops BPP family is the canonical source of ACE-domain-selective inhibitors studied in the literature
[3]
paper
BPP family structural diversity discussed; domain selectivity within ACE is an established research axis for this peptide class
doi: 10.1016/j.toxicon.2008.02.019
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.3734199106693268 boltz-2
ranking score 0.7420598864555359 boltz-2
3-letter notation
Gly-Arg-Pro-Pro-Gly-Pro-Pro-Ile-Pro-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 from snake venom (ACE inhibitor) (pep-10558, v1). PeptideModel. https://peptidemodel.com/card/pep-10558
@peptide{pep10558,
  sequence = {GRPPGPPIPP},
  target   = {ace},
  author   = {peptidemodel},
  year     = {2026},
  status   = {synthesized}
}
clinical trials 331 on ct.gov · checked 2026-05-09
ct.gov trials 331
with results 74
by phase
2phase 21phase 35phase 42no phase
by status
6completed2terminated2unknown
references 3 papers
discussion no comments
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peptidemodel.com CC-BY-SA-4.0 research only · not for human use