pe
pep-05454 v1 CC-BY-SA-4.0

IGF2 opioid receptor peptide

A brain-signaling molecule that acts on the body's opioid system, which helps control pain and mood; used only as a lab research tool.

statuscomputed targetOPRM1 length34 aa refs3
neuropeptide
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
ipTM0.632
pTM0.798
avg pLDDT71.2
ranking score0.696
STRUCTURE · PEP-05454 × OPRM1
ranking0.696
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence34 aa
15101520253034
DVSASTTVLPDDVTAYP VGKFFQYDIWKQSTQRL
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 peptide that attaches to a different part of the opioid receptor produce pain relief without the usual downsides?

Most opioid drugs lose effectiveness over time and carry addiction risk because they plug into the same exact spot on the receptor every time. If this peptide latches onto a different region, it might dampen pain signals without triggering that same cycle of tolerance, though this is still an early, unproven idea.

The hypothesis
Pep-05454 does not act as a canonical agonist at OPRM1 via the classical N-terminal Tyr pharmacophore but instead binds an allosteric or extracellular vestibule site on OPRM1, consistent with its lack of an N-terminal tyrosine and its moderate predicted interface confidence (iptm 0.63).
Why it’s plausible
Classical opioid peptides (enkephalins, endorphins, dermorphin) require a Tyr-Gly-Gly-Phe or equivalent Tyr-X-X-Phe N-terminal pharmacophore for orthosteric OPRM1 engagement. The sequence of pep-05454 begins with DVSA, placing no Tyr at the N-terminus. The aromatic-rich central cluster KFFQYDIWK (residues 20-28) contains two Phe, one Tyr, one Trp, and could engage a secondary binding surface on OPRM1 or an extracellular loop site. The moderate iptm of 0.63 from the Boltz-2 complex prediction is consistent with a non-canonical, lower-affinity interface rather than a tight orthosteric engagement.
Why it matters
If the peptide binds an allosteric site on OPRM1, it could modulate receptor signaling without the desensitization and tolerance liabilities associated with orthosteric agonists, opening a distinct therapeutic avenue compared to classical opioids.
Plausibility.52
Novelty.58
Impact.62
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceN-terminal sequence DVSA lacks the Tyr at position 1 required for classical orthosteric opioid binding; aromatic cluster KFFQYDIWK is centrally located.
[2]
structureiptm of 0.63 indicates moderate interface confidence with OPRM1, below the high-confidence threshold expected for a tight orthosteric peptide agonist.
[3]
paper
Structural studies show that peptide agonists at MOR engage specific conserved interactions in the orthosteric pocket, with N-terminal Tyr as the key anchor.
doi: 10.1038/s12276-025-01497-y
openupdated 2026-06-05

What if the receptor this peptide is supposed to act on is simply the wrong one?

If the scientific record has pointed researchers toward the wrong receptor, every experiment and dollar spent developing this peptide as an opioid drug would be wasted. Getting the target right first is the single most important step before any further work, and fixing it early could redirect effort toward the receptor where the peptide might actually work.

The hypothesis
Pep-05454 is a fragment of IGF2 that acts primarily through the IGF1 receptor (IGF1R) or the insulin receptor (INSR) rather than OPRM1, and its annotated mu-opioid receptor target is incorrect or secondary.
Why it’s plausible
The peptide name explicitly references IGF2, a growth factor that signals through IGF1R and INSR. IGF2 peptide fragments have been studied for receptor cross-reactivity. The sequence DVSASTTVLPDDVTAYPVGKFFQYDIWKQSTQRL shares features with the IGF2 C-domain region, which is known to contribute to receptor binding specificity. None of the direct reference papers report OPRM1 binding data for this specific peptide; the references are food-derived peptide reviews with general opioid receptor context. The Boltz-2 prediction was run against OPRM1, but the moderate iptm could equally reflect a mis-matched docking partner.
Why it matters
Misassignment of the primary receptor target would redirect all structure-activity and therapeutic development work toward the wrong receptor family; establishing the correct target is foundational for any downstream utility.
Plausibility.42
Novelty.53
Impact.82
Basis · grounding1 paper · 2 computed/notes
[1]
noteCard title states 'IGF2 opioid receptor peptide', explicitly linking the peptide to the IGF2 parent protein.
[2]
paper
IGF-I and IGF-II peptides show differential delivery and receptor engagement in gastrointestinal tissues, showing IGF family peptides are active in gut contexts.
doi: 10.1210/en.2002-220643
[3]
structureiptm 0.63 with OPRM1 is ambiguous and does not rule out better-fit interfaces with IGF1R or INSR.
openupdated 2026-06-05

Could a peptide derived from a food protein help people feel full and eat less, through the gut's own opioid system?

If this holds, it could lead to a food-grade ingredient, think a functional food or supplement, that helps reduce calorie intake without a prescription drug. It would work through a different biological route than existing approaches like probiotic bacteria that mimic appetite hormones, potentially offering an additional tool for people managing their weight.

The hypothesis
Pep-05454 reduces caloric intake and body weight in diet-induced obesity by acting as a gut-luminally active satiety peptide, placing it in the same functional class as ClpB-derived mimetics of alpha-MSH from Hafnia alvei, but via an opioid receptor rather than melanocortin pathway.
Why it’s plausible
The direct reference papers, including the Hafnia alvei probiotic obesity study, describe a gut-brain satiety axis where microbially or food-derived peptides reduce food intake and body weight. The IGF2 family has connections to energy homeostasis. A gut-acting opioid peptide from IGF2 could complement or parallel the melanocortin satiety pathway, since both mu and delta opioid receptors in the gut influence satiety signals. This would make pep-05454 a candidate food-grade anti-obesity ingredient distinct from melanocortin-targeting probiotics.
Why it matters
Obesity is a major unmet therapeutic need; a food-derived, gut-restricted satiety peptide with an opioid mechanism could lead to novel functional food ingredients or nutraceuticals with a favorable safety profile compared to systemic appetite suppressants.
Plausibility.37
Novelty.57
Impact.72
Basis · grounding3 papers
[1]
paper
Hafnia alvei probiotic reduces obesity and overweight via gut-brain axis; context for food-derived peptide satiety action.
doi: 10.3390/nu13020632
[2]
paper
Appetite regulation by plant-derived bioactive peptides, showing food-derived peptides are a validated class for satiety modulation.
doi: 10.1016/j.peptides.2021.170608
[3]
paper
Intestinal opioid receptors linked directly to protein-induced satiety and intestinal gluconeogenesis.
doi: 10.3389/fendo.2017.00085
openupdated 2026-06-05

Could a peptide reduce hunger by acting only inside the gut, sending a fullness signal to the brain without being absorbed?

Opioid drugs taken systemically cause addiction, breathing problems, and severe constipation because they act throughout the body and brain. A peptide too large to survive digestion intact might still flip gut-wall receptors that send a 'stop eating' message along the vagus nerve, potentially delivering an appetite-suppressing benefit with a much safer profile. This is speculative and needs direct testing.

The hypothesis
Pep-05454 mediates satiety signaling through activation of intestinal opioid receptors (mu or delta subtypes) in the enteric nervous system without requiring systemic absorption, triggering a gut-brain vagal signal that reduces food intake.
Why it’s plausible
The three direct reference papers are all about food-derived peptides, gut-brain axis satiety regulation, and the microbiota-gut-brain connection, not central opioid pharmacology. The oral-bioavailability axis hit explicitly cites evidence that some opioid peptides produce biological effects through intestinal opioid receptors without absorption. The 34-residue length of pep-05454 makes it unlikely to survive proteolysis intact during systemic absorption, but a luminal or epithelial-surface mechanism would bypass this requirement. The peptide could act on the dense opioid receptor network in the enteric plexus to suppress appetite.
Why it matters
A gut-restricted opioid mechanism would allow satiety modulation without central opioid side effects (addiction, respiratory depression, constipation from systemic exposure), making this peptide a candidate for safer appetite-suppressing food ingredients or nutraceuticals.
Plausibility.47
Novelty.38
Impact.65
Basis · grounding4 papers
[1]
paper
Opioid peptides can produce biological effects by interacting with mu, delta, and kappa opioid receptors in the GI tract without being absorbed.
doi: 10.3390/biom10070992
[2]
paper
Bioactive peptides and opioid receptors are implicated in intestinal gluconeogenesis and protein-induced satiety.
doi: 10.3389/fendo.2017.00085
[3]
paper
References context of microbiota-gut-brain axis and energy balance regulation via neuropeptide interactions.
doi: 10.3390/nu13020632
[4]
paper
Food-derived peptide cross-BBB transmission and CNS effects reviewed; gut-restricted action is a distinct plausible mechanism.
doi: 10.1021/acs.jafc.3c06518
openupdated 2026-06-05

If most of a long peptide is just inert filler, could you chop it down to the working piece and get a more useful molecule?

Long peptides are fragile, they break down in the gut, are expensive to make, and rarely become medicines on their own. If the biologically active part turns out to be just the aromatic-rich tail end of the sequence, a shorter version could survive digestion better and be a realistic starting point for a drug or supplement, though activity of the trimmed version still needs to be confirmed in lab experiments.

The hypothesis
Shortening pep-05454 to the C-terminal aromatic core FFQYDIWKQSTQRL (14 residues) will retain OPRM1 or OPRD1 binding activity while substantially improving proteolytic stability and synthetic accessibility, because the N-terminal 20 residues lack known opioid pharmacophoric features.
Why it’s plausible
Opioid peptide SAR consistently shows that the key pharmacophoric residues can be isolated in short fragments. The segment KFFQYDIWK (residues 20-28 of the full peptide) contains all aromatic residues and is the only region with structural similarity to known receptor-binding motifs. The N-terminal 19 residues (DVSASTTVLPDDVTAYPVG) are predominantly hydrophilic and aliphatic with no classical opioid pharmacophore elements. For a 34-residue peptide, proteolytic vulnerability is high; the oral bioavailability axis hits confirm this concern. A 14-residue C-terminal fragment would be more amenable to chemical synthesis and could be tested as a minimal pharmacophore.
Why it matters
Truncation to a minimal active fragment is the standard first step in converting a long food-derived peptide into a drug-like lead; if the 14-mer retains activity, it opens a clear medicinal chemistry path toward analogs with improved ADME properties.
Plausibility.43
Novelty.35
Impact.57
Basis · grounding2 papers · 1 computed/note
[1]
sequenceAromatic residues Phe21, Phe22, Tyr23, Trp26 are all concentrated in the C-terminal half; the N-terminal 19 residues contain only one aromatic (Tyr at position 17 within the AYPVG turn).
[2]
paper
Milk protein-derived opioid receptor ligands are reviewed; minimal opioid fragments from food proteins are a validated SAR approach.
doi: 10.1002/biot.200700045
[3]
paper
High cost of peptide synthesis motivates truncation to minimal active sequences for clinical and commercial viability.
doi: 10.1038/nbt1267
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.6317421793937683 boltz-2
ranking score 0.6963351368904114 boltz-2
structural qualityopenfold3
metricvaluenote
gpde1.063global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Asp-Val-Ser-Ala-Ser-Thr-Thr-Val-Leu-Pro-Asp-Asp-Val-Thr-Ala-Tyr-Pro-Val-Gly-Lys-Phe-Phe-Gln-Tyr-Asp-Ile-Trp-Lys-Gln-Ser-Thr-Gln-Arg-Leu
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). IGF2 opioid receptor peptide (pep-05454, v1). PeptideModel. https://peptidemodel.com/card/pep-05454
@peptide{pep05454,
  sequence = {DVSASTTVLPDDVTAYPVGKFFQYDIWKQSTQRL},
  target   = {oprm1},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 5 by signal overlap
references 3 papers
discussion no comments
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