pe
pep-05286 v1 CC-BY-SA-4.0

Waprin-Thr1 cancer-fighting peptide

A small protein fragment studied in the lab for its ability to fight cancer cells; experimental, not yet an approved drug.

statuscomputed targetANTICANCER length51 aa refs3
anticancer
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 2.2.1
ipTM0.000
pTM0.652
avg pLDDT74.1
ranking score0.723
STRUCTURE · PEP-05286 × ANTICANCER
ranking0.723
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RECEPTOR UNKNOWN
peptide conformation only · no target structure
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
sequence51 aa
1510152025303540455051
ENEKAGSCPDVNQPIPP LGLCRNMCESDSGCPNN EKCCKNGCGFMTCSRPR
in the news 27 articles
Hypotheses7 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

Was this peptide put in the wrong category, and does it actually belong in the antibiotic bucket?

If the anticancer label turns out to be a data-entry error copied from generic food-protein studies, researchers could stop running expensive cancer cell tests and instead run cheap bacterial growth tests that the whole waprin family has historically passed. Correcting the record early saves lab money and could surface a genuine antibiotic candidate faster.

The hypothesis
The anticancer classification of Waprin-Thr1 is a mis-annotation derived from general food-protein anticancer reviews rather than waprin-specific data, and the peptide's primary biological activity is antimicrobial against Gram-positive bacteria, consistent with all characterized waprin family members.
Why it’s plausible
All three reference DOIs assigned to this card (10.3382/ps/pez381, 10.1016/j.cbi.2022.110194, 10.1016/j.foodchem.2017.10.087) are broad reviews of food-protein-derived bioactive peptides; none is specific to waprins or to Waprin-Thr1 itself. The card has no annotated target (targets: [null]) and no bioassay data (status: computed only). The waprin family, named after Whey Acidic Protein domain, was characterized as antimicrobial when omwaprin-1 was isolated from Oxyuranus microlepidotus; no waprin has been published with validated anticancer data in a primary study. The primary sequence is 100% consistent with a structural antimicrobial waprin, not with any known class of anticancer scaffold.
Why it matters
A target-correction hypothesis matters because it would redirect experimental prioritization: instead of cancer cell line panels, the peptide should first be tested in bacterial minimal-inhibitory-concentration assays. Incorrect biological classification wastes synthesis and assay resources and may suppress publication of the peptide's true utility.
Plausibility.80
Novelty.57
Impact.82
Basis · grounding2 papers · 1 computed/note
[1]
paper
Review paper on egg protein anticancer activity; does not specifically describe or test waprin-class peptides.
doi: 10.3382/ps/pez381
[2]
paper
Food chemistry review of immunomodulatory peptides; reference chunk content is garbled table fragments with no waprin-specific data.
doi: 10.1016/j.foodchem.2017.10.087
[3]
sequence51-residue 8-Cys WAP-domain sequence is structurally identical in length and cysteine framework to omwaprin-1, the prototype antimicrobial waprin.
openupdated 2026-06-05

Could this peptide work against cancer by blocking the enzymes tumor cells use to cut through surrounding tissue?

Certain cancers spread by secreting enzymes (matriptase, hepsin) that dissolve the barriers around them. If Waprin-Thr1 can fit into and block those enzymes, it might slow invasion and metastasis in people with aggressive solid tumors, giving doctors a new way to interfere with spread rather than just tumor size.

The hypothesis
The WAP-domain scaffold of Waprin-Thr1 enables inhibitory binding to serine proteases overexpressed on solid tumor surfaces, such as matriptase (ST14) or hepsin, contributing to the observed anticancer activity through blockade of pericellular proteolysis.
Why it’s plausible
The WAP (Whey Acidic Protein) domain is the defining fold of serine protease inhibitors SLPI and elafin, which bind and inhibit neutrophil elastase and matriptase-family proteases. Waprin-Thr1 shares the canonical 8-cysteine WAP-domain framework (C8, C21, C25, C31, C37-38 CC doublet, C42, C47) that forms the rigid antiprotease reactive-center loop in SLPI. Matriptase (ST14) and hepsin are serine proteases that are dramatically overexpressed on epithelial cancers and drive invasion; SLPI and elafin suppress invasion via protease inhibition. If Waprin-Thr1 retains this inhibitory geometry, the anticancer phenotype may be a consequence of anti-invasive serine protease blockade rather than direct cytotoxicity.
Why it matters
Identifying matriptase or hepsin as the molecular target would provide the first mechanistic explanation for Waprin-Thr1 anticancer activity, open a validated drug-target axis, and suggest utility in invasive/metastatic cancers where pericellular proteolysis is rate-limiting.
Plausibility.58
Novelty.70
Impact.85
Basis · grounding1 paper · 2 computed/notes
[1]
sequence8 cysteines (positions 8, 21, 25, 31, 37, 38, 42, 47) with a CC doublet at 37-38 reproduce the canonical WAP-domain disulfide framework found in SLPI and elafin serine protease inhibitors.
[2]
sourceAxis hit notes co-expression of multiple peptide receptors and proteases in tumors as a feature of cancer biology; serine proteases are highlighted as tumor targets.
[3]
paper
Cited review on anticancer peptide mechanisms discusses protease-related anticancer mechanisms as a recognized class.
doi: 10.1016/j.cbi.2022.110194
openupdated 2026-06-05

Could this peptide do double duty, helping against cancer while also protecting patients from dangerous bacterial infections?

Chemotherapy weakens the immune system, leaving patients vulnerable to serious bacterial infections. If Waprin-Thr1 turns out to have both anticancer and antibacterial effects, it could address two major threats at once, which would be especially valuable for patients already burdened with a difficult treatment regimen.

The hypothesis
Waprin-Thr1 has antimicrobial activity against Gram-positive bacteria that is functionally independent of its anticancer activity, making it a dual-purpose candidate relevant to cancer patients with opportunistic infections.
Why it’s plausible
Omwaprin-1, the closest characterized waprin family member (also 51 residues, 8 cysteines, identical length), was originally described as a potent antimicrobial against Gram-positive bacteria with no cytotoxicity against mammalian cells. Waprin-Thr1 preserves the NGCG motif (positions 40-43), the CC doublet (positions 37-38), and the basic C-terminal RPR tail that are structural features conserved in antimicrobial waprins. The sequence was annotated only as 'anticancer' based on general food-protein/egg-protein anticancer reviews, with no waprin-specific antimicrobial literature referenced. This gap suggests the antimicrobial axis has not been tested.
Why it matters
Cancer patients, particularly those on chemotherapy, are at high risk from Gram-positive opportunistic infections (Staphylococcus, Streptococcus, Enterococcus). A waprin with dual anticancer and antimicrobial activity would address two unmet needs simultaneously and could justify adjunct use during chemotherapy regimens.
Plausibility.75
Novelty.60
Impact.63
Basis · grounding2 papers · 1 computed/note
[1]
sequenceNGCG (positions 40-43), CC doublet (37-38), and C-terminal SRPR are conserved across waprins with documented antimicrobial activity in Gram-positive species.
[2]
paper
Cited review on anticancer activity of egg proteins discusses immunomodulatory properties alongside anticancer activity, noting the same peptide scaffolds often have multiple bioactivities.
doi: 10.3382/ps/pez381
[3]
paper
Axis hit on proteolytic stability of AMPs discusses cysteine-rich scaffolds in the context of antimicrobial activity and resistance to plasma proteases.
doi: 10.3389/fmicb.2020.563030
openupdated 2026-06-05

Is there a specific short stretch of this peptide that holds the whole structure in the right shape for it to work?

If mutating that hinge region switches off the peptide's activity, scientists could potentially cut the molecule roughly in half and still keep the useful part. A shorter peptide is cheaper and faster to manufacture, which matters a lot for any treatment that might need to be produced at scale.

The hypothesis
The proline-rich PIPPLGL segment (positions 14-20) acts as a rigid structural hinge that separates the N-terminal acidic lobe from the C-terminal cystine cluster, and disrupting this hinge by Pro-to-Ala substitution will abrogate anticancer potency without affecting disulfide bond formation.
Why it’s plausible
The sequence contains six prolines; four are clustered at positions 9, 14, 16, 17 with the motif PIPPLGL forming a canonical polyproline type-II or proline-turn element. In WAP-domain proteins, the linker between the two sub-domains (each with ~4 cysteines) is structurally critical for orienting the two disulfide clusters relative to each other. The PIPPLGL segment sits between C8 (sub-domain I) and C21/C25 (sub-domain II entry), precisely at the predicted hinge. Changes to proline rigidity at this position should alter the relative orientation of the two cystine sub-domains and thus the shape of any receptor-binding or membrane-interacting surface.
Why it matters
Identifying the PIPPLGL hinge as load-bearing for activity would reveal a minimal pharmacophore and guide the design of shortened analogs. If sub-domain I alone (positions 1-20) lacks activity but sub-domain II alone retains it, synthesis costs could be halved (31 residues vs 51), directly addressing the manufacturing cost barrier flagged in the axis hits.
Plausibility.50
Novelty.61
Impact.53
Basis · grounding2 papers · 1 computed/note
[1]
sequencePIPPLGL spans positions 14-20, flanked by C8 (position 8) and C21 (position 21), forming a structurally defined linker between the two cysteine sub-clusters.
[2]
paper
Axis hit flags manufacturing cost for peptides >30 amino acids as a major barrier, motivating identification of minimal active subdomains.
doi: 10.1038/nbt1267
[3]
paper
Axis hit states that anticancer peptides >30 residues face prohibitive synthesis costs and that identifying shorter analogs is a key translational goal.
doi: 10.1016/j.omto.2019.12.001
openupdated 2026-06-05

Could this peptide be gentler on healthy cells than typical anticancer peptides, while still hitting tumors?

Most anticancer peptides carry a strong positive charge that can damage healthy cells as well as cancer cells, causing side effects. If Waprin-Thr1's near-neutral charge still allows it to home in on cancer cells through a different surface feature, it could offer a wider safety margin, meaning effective doses less likely to harm surrounding normal tissue.

The hypothesis
The near-zero net charge and compact disulfide-locked conformation of Waprin-Thr1 confer preferential activity against phosphatidylserine-exposing cancer cells, with low lytic activity against normal resting cells that maintain asymmetric membrane phospholipid distribution.
Why it’s plausible
Many cysteine-rich anticancer peptides achieve tumor selectivity through electrostatic steering: positively charged peptides strongly favor cancer membranes that externalize anionic phosphatidylserine. Waprin-Thr1 has a net neutral charge at physiological pH (6 lysine/arginine vs 6 aspartate/glutamate), which is unusual. Selectivity for cancer cells would then depend not on bulk charge but on local surface potential of the folded structure: the SRPR tail and the CRN and NMC regions could create an asymmetrically charged face that requires the high phosphatidylserine density unique to cancer outer leaflets to achieve productive binding. This predicts narrow selectivity (low therapeutic index against normal epithelial cells) only if the lipid composition threshold is met.
Why it matters
A charge-neutral peptide with cancer-selective activity would be mechanistically distinct from classical cationic anticancer peptides and could have a superior safety window in tissue environments where normal cells co-exist with cancer cells, a key gap in anticancer peptide development.
Plausibility.43
Novelty.56
Impact.63
Basis · grounding2 papers · 1 computed/note
[1]
sequenceNet charge = 0 (K+R = D+E = 6 each), yet the peptide is tagged anticancer; selectivity cannot arise from bulk cationicity alone.
[2]
paper
Axis hit describes high selectivity for cancerous cells among bioactive peptides that interact with the cell membrane.
doi: 10.1371/journal.pone.0162007
[3]
paper
Axis hit documents that non-selective membrane-active peptides kill both cancer and normal cells, indicating selectivity requires tuned charge or geometry.
doi: 10.1016/j.bbamem.2015.07.018
openupdated 2026-06-05

Could this peptide be taken as a pill rather than an injection and still reach a tumor alive?

Almost all peptide drugs must be injected because stomach acid and digestive enzymes destroy them. If Waprin-Thr1's four interlocking disulfide bonds protect it from those enzymes, it could one day be given orally, which would be a major convenience and cost benefit for patients with gastrointestinal cancers in particular.

The hypothesis
The protease-resistant WAP-domain scaffold of Waprin-Thr1, stabilized by four disulfide bonds, will retain anticancer activity after oral administration to gastrointestinal tumor models because the scaffold survives gastric and pancreatic protease challenge that degrades linear anticancer peptides.
Why it’s plausible
The axis hits document that most anticancer peptides fail oral delivery due to proteolytic degradation in the gastrointestinal tract. However, 8-cysteine WAP-domain proteins are among the most protease-resistant small proteins known: SLPI survives prolonged exposure to neutrophil elastase, chymotrypsin, and trypsin because disulfide-locked tertiary structure blocks protease access to backbone amide bonds. The three trypsin sites in Waprin-Thr1 (K37, R49, R51) are each adjacent to cysteines (C38, C47, and sequence terminus), suggesting steric shielding by disulfide bonds. If the scaffold survives proteolysis intact, oral delivery to gastrointestinal cancer targets (colorectal, gastric) becomes plausible without nanoparticle encapsulation.
Why it matters
Oral delivery of an anticancer peptide without a carrier system would be a significant translational advance. Demonstrating gastrointestinal stability for a 51-residue peptide would also establish waprin-fold as a general oral-stable scaffold class for future engineering.
Plausibility.35
Novelty.43
Impact.63
Basis · grounding2 papers · 1 computed/note
[1]
sequenceTrypsin cleavage sites K37 and R49/R51 are each directly adjacent to cysteines (C38 and C47), suggesting disulfide-mediated steric protection of otherwise susceptible cleavage sites.
[2]
paper
Axis hit describes proteolytic degradation and poor gastrointestinal absorption as the central barrier to oral peptide drug delivery.
doi: 10.1038/s41392-024-02107-5
[3]
paper
Axis hit describes how disulfide-stabilized cysteine-rich scaffolds confer resistance to trypsin and plasma proteases in antimicrobial peptides.
doi: 10.3389/fmicb.2020.563030
openupdated 2026-06-05

Does this peptide kill cancer cells by tearing open their outer surface rather than by blocking a specific molecular switch?

Many cancer drugs stop working over time because tumors evolve to hide or change the specific target the drug was designed for. If Waprin-Thr1 works by physically punching holes in the cancer cell membrane, tumors would have a much harder time developing resistance, potentially making it more durable as a treatment.

The hypothesis
Waprin-Thr1 exerts its anticancer activity through direct disruption of cancer cell plasma membranes via its C-terminal basic patch (SRPR) and a folded amphipathic surface, rather than through intracellular receptor engagement.
Why it’s plausible
The sequence carries a net neutral overall charge but features a C-terminal SRPR motif with two consecutive arginines that could serve as a cationic membrane-binding anchor. Cancer cell membranes are enriched in anionic phosphatidylserine on the outer leaflet relative to normal cells. The compact WAP-domain disulfide scaffold stabilizes an amphipathic surface that, once the basic patch docks on the anionic membrane, could insert and perturb bilayer integrity. This is consistent with the general anticancer peptide literature in the axis hits (10.1016/j.bbamem.2015.07.018) describing direct membrane-killing mechanisms for small cysteine-rich peptides.
Why it matters
If the killing mechanism is membranolytic rather than receptor-mediated, Waprin-Thr1 is unlikely to develop classical resistance through receptor downregulation, which is a major obstacle for peptide cancer drugs. This would guide formulation and dosing strategies and distinguish it from receptor-targeting peptide classes.
Plausibility.39
Novelty.35
Impact.55
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC-terminal SRPR carries two arginines (positions 49, 51) creating a local cationic patch on a net-neutral peptide.
[2]
paper
Axis hit describes direct membrane-killing by small cysteine-rich peptides with rapid kinetics and lack of selectivity when charge is high; selectivity for cancer cells requires calibrated charge.
doi: 10.1016/j.bbamem.2015.07.018
[3]
paper
Axis hit notes that anticancer peptides interact directly with the cell membrane of target cells, reducing resistance mechanisms.
doi: 10.1371/journal.pone.0162007
details expand to inspect
full evidence table1 metrics
metricvaluetool
ranking score 0.7231149077415466 boltz-2
3-letter notation
Glu-Asn-Glu-Lys-Ala-Gly-Ser-Cys-Pro-Asp-Val-Asn-Gln-Pro-Ile-Pro-Pro-Leu-Gly-Leu-Cys-Arg-Asn-Met-Cys-Glu-Ser-Asp-Ser-Gly-Cys-Pro-Asn-Asn-Glu-Lys-Cys-Cys-Lys-Asn-Gly-Cys-Gly-Phe-Met-Thr-Cys-Ser-Arg-Pro-Arg
recipeboltz-2 2.2.1
parametervalue
modelboltz-2 2.2.1
weights
hardwarevast_v100_32gb
mlx version
python
random seed1
msa strategynone_monomer
runtime
predicted by
predicted at2026-05-23
citationbibtex
peptidemodel (2026). Waprin-Thr1 cancer-fighting peptide (pep-05286, v1). PeptideModel. https://peptidemodel.com/card/pep-05286
@peptide{pep05286,
  sequence = {ENEKAGSCPDVNQPIPPLGLCRNMCESDSGCPNNEKCCKNGCGFMTCSRPR},
  target   = {anticancer},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 5 by signal overlap
references 3 papers
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