pe
pep-05202 v1 CC-BY-SA-4.0

Anionic antimicrobial peptide 2 anticancer peptide

A lab-studied peptide that may help fight cancer cells; experimental, not yet an approved drug.

statusbioassayed targetANTICANCER length60 aa refs1
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 · 0 verified on platform
prediction metrics boltz-2 2.2.1
ipTM0.000
pTM0.516
avg pLDDT70.7
ranking score0.669
STRUCTURE · PEP-05202 × ANTICANCER
ranking0.669
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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
sequence60 aa
151015202530354045505560
ETESTPDYLKNIQQQLEEYT KNFNTQVQNAFDSDKIKSEV NNFIESLGKILNTEKKEAPK
in the news 27 articles
Hypotheses4 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

If only one end of a long molecule does the actual work, could we just use that end?

If the short tail of this peptide turns out to be all that matters for killing cancer cells, researchers could manufacture it at a fraction of the current cost. That could make it far more practical to develop as a drug candidate.

The hypothesis
The C-terminal amphipathic segment FIESLGKILNTEKKEAPK (residues 43-60) constitutes the minimal functional domain of Gm anionic peptide 2 and retains full anticancer potency independently of the N-terminal anionic domain.
Why it’s plausible
The full 60-residue sequence divides into two structurally distinct regions. Residues 1-42 are enriched in acidic and polar residues (E, D, Q, N, T) and are likely disordered in solution. Residues 43-60 (FIESLGKILNTEKKEAPK) contain a hydrophobic face (F43, I44, L, G, I, L) and a cationic face (K50, K52, K53, K60) consistent with an amphipathic alpha-helix. Amphipathic C-terminal helices in cecropins and related insect AMPs are well established as the membrane-active modules, while N-terminal regions modulate solubility and target specificity. If the N-terminal acidic region primarily solubilizes the peptide and prevents self-aggregation in hemolymph while the C-terminal helix drives bilayer disruption, a truncated C-terminal peptide should be as potent or more potent than the full sequence. This would mirror findings for cecropin-A and magainin hybrids.
Why it matters
Identifying a shorter active core would reduce synthesis cost substantially (from 60 to ~18 residues), addressing the manufacturing cost barrier noted in the literature, and would establish this insect anionic peptide as a scaffold for short amphipathic anticancer peptide design.
Plausibility.57
Novelty.40
Impact.72
Basis · grounding2 papers · 1 computed/note
[1]
sequenceHydrophobic-cationic amphipathic pattern in C-terminal FIESLGKILNTEKKEAPK vs. disordered acidic N-terminal region
[2]
paper
High manufacturing cost of long peptides is the key barrier to development; shorter active cores have significant value
doi: 10.1038/nbt1267
[3]
paper
Trend toward shorter antimicrobial peptides to reduce synthesis cost without losing activity
doi: 10.1038/srep42994
openupdated 2026-06-05

Most cancer-targeting peptides are positively charged, so how could a negatively charged one still find tumor cells?

Many cancer cells wear a specific fat molecule (phosphatidylserine) on their outer surface that healthy cells keep hidden inside. If this negatively charged peptide latches on to that instead of using charge attraction, it could open a whole new way to target tumors selectively, for people who need treatments that spare healthy tissue.

The hypothesis
Gm anionic peptide 2 kills cancer cells through a membrane-disruption mechanism that depends on the elevated phosphatidylserine exposure on tumor cell outer leaflets rather than electrostatic attraction, distinguishing it mechanistically from cationic AMPs.
Why it’s plausible
The sequence carries multiple acidic residues (E1, E13, E14, E18, D7, D31, D34) and relatively few basic residues, yielding a net anionic or near-neutral charge at pH 7.4. Classical cationic AMPs exploit the negatively charged bacterial or cancer-cell membranes via electrostatic attraction. An anionic peptide achieving anticancer activity must instead rely on hydrophobic insertion or on specific recognition of positively charged or zwitterionic lipid head groups exposed on cancer cells, such as phosphatidylserine (PS). PS is constitutively flipped to the outer leaflet in many cancer cell types, creating a locally cationic environment that could attract an anionic peptide. The C-terminal stretch FIESLGKILNTEKKEAPK contains a hydrophobic cluster (FI, LGK, IL) flanked by cationic K residues, consistent with a tilted or oblique amphipathic insertion angle that would favor PS-rich domains over bulk bilayer.
Why it matters
If confirmed, this would establish a PS-recognition mechanism for anionic insect-derived AMPs with anticancer activity, opening a selectivity rationale that is completely distinct from the charge-inversion logic of cationic peptides and suggesting synergy with PS-targeting agents.
Plausibility.47
Novelty.43
Impact.62
Basis · grounding2 papers · 1 computed/note
[1]
sequenceNet anionic/near-neutral charge from multiple E and D residues; C-terminal amphipathic cluster FIESLGKILNTEKKEAPK
[2]
paper
Peptide purified from G. mellonella immune hemolymph and shown to have antimicrobial activity distinct from other peptides in the same preparation
doi: 10.1016/j.peptides.2006.11.010
[3]
paper
Anticancer activity of AMPs is linked to cancer-cell-specific lipid asymmetry including PS exposure
doi: 10.1371/journal.pone.0162007
openupdated 2026-06-05

Can you build a peptide drug that stays switched off in healthy tissue but switches on inside a tumor?

Tumors have a distinct chemical environment, including enzymes and acidity not found in healthy tissue. If a neutralizing cap can be designed to fall off only in that environment, it could allow a potent cancer-killing peptide to travel through the body safely and activate only where it is needed, reducing side effects for patients.

The hypothesis
Conjugating the N-terminal acidic domain of Gm anionic peptide 2 to a known cationic anticancer peptide via a disulfide or cathepsin-cleavable linker will create a tumor-microenvironment-activated prodrug that is inactive at physiological pH but releases the cationic peptide upon cleavage in the acidic, cathepsin-rich tumor milieu.
Why it’s plausible
The N-terminal segment (ETESTPDYLKNIQQQLEEYTK) is multiply acidic and could act as a charge-neutralizing mask when fused to a cationic AMP, suppressing membrane activity in healthy tissue where serum proteases are limited. Solid tumors overexpress cathepsin B and cathepsin D and have extracellular pH around 6.5-6.8. A cathepsin-sensitive linker would be cleaved preferentially in the tumor microenvironment, releasing the cationic warhead. The tyrosine at position 9 (Y in ETESTPDYLK) is a natural site for photocrosslinking or chemical functionalization, and the two adjacent lysines in TEKKEAPK at the C-terminus provide conjugation handles. This approach leverages the existing anionic character of the peptide rather than engineering it de novo.
Why it matters
A tumor-microenvironment-activated prodrug design based on an insect anionic AMP scaffold would be a novel prodrug concept for cancer-targeting peptides, directly addressing the selectivity and toxicity concerns that currently limit translation of cationic AMPs.
Plausibility.42
Novelty.40
Impact.58
Basis · grounding2 papers · 1 computed/note
[1]
sequenceMultiply acidic N-terminal segment ETESTPDYLKNIQQQLEEYTK; tyrosine at position 9; C-terminal lysines at positions 52, 53, 60 as conjugation handles
[2]
paper
TAT-linked AMP fusions improve stability and transmembrane delivery but can reduce specificity, showing linker design is a key variable
doi: 10.7150/ijbs.23419
[3]
paper
AMP-based anticancer agents are valued for low multi-drug-resistance risk, motivating prodrug strategies to add selectivity
doi: 10.3390/toxins7124878
openupdated 2026-06-05

Some molecules only become dangerous to cells after several copies lock together, so could that be what makes this peptide work?

If the peptide needs to cluster before it can punch holes in cancer cell membranes, understanding that step could help researchers design more potent versions that assemble faster, or dial back activity in healthy tissue. It would also explain why a negatively charged peptide can kill cancer cells at all, a puzzle that currently limits confidence in this class of molecules.

The hypothesis
The central glutamine-rich segment NIQQQLEEYTK of Gm anionic peptide 2 forms a coiled-coil or LARKS-like steric-zipper interaction that drives peptide oligomerization at the membrane surface, and this oligomerization is required for cytotoxic pore formation.
Why it’s plausible
The motif NIQQQLEEYTK at positions 11-21 contains three consecutive glutamines (QQQ) flanked by asparagine (N) and glutamate (E) residues. In the context of human proteins, polyglutamine and NxQ-rich segments are known to drive steric-zipper or LARKS-type interactions leading to fibril or oligomer formation. Several pore-forming AMPs (e.g., alamethicin, pardaxin) oligomerize via coiled-coil or barrel-stave interactions at the membrane interface. If the QQQ segment of Gm anionic peptide 2 nucleates lateral self-association once the peptide adsorbs to a membrane, the resulting oligomeric complex could insert to form a lipid-perturbing pore that individual monomers cannot form. The presence of a C-terminal amphipathic region (FIESLGKILNTEKKEAPK) would provide the transmembrane anchor for such a barrel-stave or toroidal pore.
Why it matters
Defining oligomerization dependence on the QQQ motif would (a) explain why this 60-residue anionic peptide achieves cytotoxicity despite its charge, (b) predict that truncation of the N-terminal segment reduces potency, and (c) suggest engineering strategies that tune self-association for improved activity.
Plausibility.35
Novelty.53
Impact.48
Basis · grounding2 papers · 1 computed/note
[1]
sequenceTriglutamine run QQQ at positions 13-15 within an asparagine/glutamate-rich segment NIQQQLEEYTK
[2]
paper
Two-state model of AMP action links membrane-surface oligomerization to pore formation
doi: 10.1021/bi301426j
[3]
paper
Amphipathic structures are key to anticancer mechanisms derived from AMPs
doi: 10.1007/s13277-015-3402-6
details expand to inspect
full evidence table1 metrics
metricvaluetool
ranking score 0.6690128445625305 boltz-2
3-letter notation
Glu-Thr-Glu-Ser-Thr-Pro-Asp-Tyr-Leu-Lys-Asn-Ile-Gln-Gln-Gln-Leu-Glu-Glu-Tyr-Thr-Lys-Asn-Phe-Asn-Thr-Gln-Val-Gln-Asn-Ala-Phe-Asp-Ser-Asp-Lys-Ile-Lys-Ser-Glu-Val-Asn-Asn-Phe-Ile-Glu-Ser-Leu-Gly-Lys-Ile-Leu-Asn-Thr-Glu-Lys-Lys-Glu-Ala-Pro-Lys
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). Anionic antimicrobial peptide 2 anticancer peptide (pep-05202, v1). PeptideModel. https://peptidemodel.com/card/pep-05202
@peptide{pep05202,
  sequence = {ETESTPDYLKNIQQQLEEYTKNFNTQVQNAFDSDKIKSEVNNFIESLGKILNTEKKEAPK},
  target   = {anticancer},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
references 1 papers
[1] source scaffold
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