pe
pep-05356 v1 CC-BY-SA-4.0

Plasticin-S1 anticancer peptide

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

statuscomputed targetANTICANCER length48 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
pTM0.365
avg pLDDT67.4
ranking score0.613
STRUCTURE · PEP-05356 × ANTICANCER
ranking0.613
?
RECEPTOR UNKNOWN
peptide conformation only · no target structure
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
sequence48 aa
15101520253035404548
EEEKREGENEKEQEDD NQSEEKRGLVSDLLST VTGLLGNLGGGGLKKI
in the news 27 articles
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

Could this peptide stay safely switched off while circulating in the body, then switch on only when it reaches a tumor?

If confirmed, this would help explain why the peptide might be given systemically without destroying healthy tissue along the way. It could also guide engineers to build smarter drug versions that release their toxic payload only inside tumors, for people with cancers that are hard to target precisely.

The hypothesis
The acidic N-terminal domain (EEEKREGENEKEQEDDNQSEEK) of Plasticin-S1 acts as an autoinhibitory cap that keeps the peptide soluble and inactive in solution, with membrane-contact-driven displacement of this domain required to expose the lytic C-terminal segment.
Why it’s plausible
The N-terminus carries at least 8 glutamate/aspartate residues and only 3 basic residues (K, R, K), giving it a strong net negative charge at physiological pH. This acidic tract could fold back and electrostatically shield the cationic, hydrophobic C-terminus through intramolecular interaction, suppressing aggregation and premature membrane activity in the bloodstream. At the cancer cell membrane surface, the local positive-charge environment (phosphatidylserine headgroups are negative, but membrane potential and cationic lipid domains can locally shift electrostatics) or the crowding effect could displace the N-terminal cap, triggering C-terminal membrane insertion. This autoinhibitory architecture is structurally analogous to latent antimicrobial peptides that require pH or lipid-triggered unmasking.
Why it matters
Confirming this mechanism would explain why the peptide tolerates systemic administration without off-target lysis, and would provide a rational basis for engineering linker-cleavable prodrug versions that release only the lytic C-terminal helix at the tumor microenvironment.
Plausibility.65
Novelty.60
Impact.70
Basis · grounding3 computed/notes
[1]
sequenceResidues 1-22 (EEEKREGENEKEQEDDNQSEEK): net charge approximately -4 to -5 at pH 7.4; residues 23-48 (RGLVSDLLSTVTGLLGNLGGGGLKKI): net charge approximately +3, hydrophobic.
[2]
structureBoltz-2 structure prediction was computed; a compact conformation with the N-terminal acidic region folded against the C-terminal hydrophobic segment would be consistent with autoinhibition.
[3]
sourceHEXIM1 BR peptide shows safety because cytotoxicity depends on intracellular localization, illustrating how compartment-dependent activation is a known safety mechanism for anticancer peptides.
openupdated 2026-06-05

If only the tail end of this peptide does the killing, could we just use that part and skip the rest?

Shorter peptides are far cheaper to manufacture and easier to chemically modify into drugs. If the trimmed version works as well, or better, it could meaningfully speed up and lower the cost of turning this compound into a real medicine for cancer patients.

The hypothesis
Removing or truncating the acidic N-terminal domain (residues 1-22) of Plasticin-S1 to yield the isolated C-terminal segment (RGLVSDLLSTVTGLLGNLGGGGLKKI) produces a shorter peptide with equal or superior membrane-lytic potency against cancer cells and improved manufacturability, because the N-terminal domain contributes steric bulk without providing lytic function.
Why it’s plausible
The full 48-residue sequence is near the upper limit of cost-effective solid-phase peptide synthesis. Axis hits note that SPPS becomes prohibitively expensive and prone to aggregation above 50 residues. The N-terminal acidic domain (22 residues) is predicted to be the solubility-enhancing and possibly autoinhibitory element; the C-terminal 26-residue segment contains all hydrophobic and amphipathic features associated with membrane activity. If autoinhibition is confirmed, truncation would increase potency. If the N-terminus only provides solubility, truncation would yield a peptide requiring formulation but with equal killing efficiency. Either way, a 26-residue C-terminal fragment would be substantially cheaper to synthesize and would allow systematic structure-activity work.
Why it matters
Defining the minimal active fragment is the necessary precursor to medicinal-chemistry optimization. A 26-residue active core with demonstrated potency could be cyclized, stapled, or conjugated to tumor-homing moieties, accelerating the path from computational design to clinical candidate.
Plausibility.71
Novelty.42
Impact.76
Basis · grounding2 papers · 1 computed/note
[1]
sequenceResidues 23-48 (RGLVSDLLSTVTGLLGNLGGGGLKKI) contain all hydrophobic, amphipathic, and cationic C-terminal features; residues 1-22 are predominantly acidic with no hydrophobic core.
[2]
paper
SPPS cost and length limitations are cited as major barriers; peptides should be kept under 50 residues; shorter sequences reduce manufacturing cost significantly.
doi: 10.1038/s41467-023-37003-z
[3]
paper
Anticancer and immunomodulatory egg peptides are typically short fragments derived from larger proteins, supporting the principle that minimal active domains retain parent activity.
doi: 10.3382/ps/pez381
openupdated 2026-06-05

Could this peptide work on cancers that have already stopped responding to standard chemotherapy?

Many cancers eventually become resistant to chemotherapy by developing pumps that eject drugs before they can act. Because Plasticin-S1 attacks the cell's outer surface rather than entering the cell, those pumps could be irrelevant to it. If this holds, it could offer a new option for patients whose cancer has stopped responding to existing treatments.

The hypothesis
Plasticin-S1 is effective against cancer cells that have acquired resistance to conventional chemotherapy through ABC-transporter-mediated drug efflux, because its membrane-lytic mechanism is independent of intracellular drug accumulation and cannot be countered by efflux pump upregulation.
Why it’s plausible
Multidrug resistance in cancer is predominantly mediated by overexpression of P-glycoprotein (ABCB1) and related ABC transporters, which pump small-molecule drugs out of cells. Membrane-active peptides that kill by disrupting the lipid bilayer are not substrates for these transporters; their mechanism of action occurs at the membrane surface before any intracellular entry is required. Plasticin-S1's bipartite structure -- large (48 aa), charged, and amphipathic -- makes it a very poor substrate for ABC transporters by size and charge alone. Cancer cells that become resistant to taxanes, anthracyclines, or platinum compounds by overexpressing P-gp would retain their membrane PS exposure and would remain equally susceptible to lytic peptides.
Why it matters
Demonstrating activity against MDR cell lines would position Plasticin-S1 as a salvage-therapy candidate for refractory cancers, a high-unmet-need niche where even modest efficacy justifies clinical development. It would also motivate combination studies pairing this peptide with first-line agents to delay resistance emergence.
Plausibility.76
Novelty.25
Impact.63
Basis · grounding2 papers · 1 computed/note
[1]
paper
Anticancer peptide mechanisms review explicitly discusses membrane-lytic mechanism as a route to bypassing classical drug resistance.
doi: 10.1016/j.cbi.2022.110194
[2]
paper
Anticancer peptides are noted to induce less resistance because they act directly on the membrane rather than on intracellular targets.
doi: 10.1371/journal.pone.0162007
[3]
sequence48 aa, MW approximately 5 kDa, amphipathic -- physicochemical properties that preclude ABC-transporter-mediated efflux.
openupdated 2026-06-05

Could a single compound be useful against both antibiotic-resistant infections and cancer?

Antibiotic-resistant infections like MRSA are a growing crisis with very few new treatments in development. If Plasticin-S1 turns out to fight both bacteria and cancer cells by the same mechanism, preclinical safety and dosing studies could serve both purposes at once, potentially cutting the cost and time of developing it for either use.

The hypothesis
Plasticin-S1 exhibits antimicrobial activity against drug-resistant Gram-positive bacteria (MRSA, VRE) through the same membrane-disruption mechanism responsible for its anticancer activity, because its cationic C-terminal amphipathic segment matches the structural requirements for disruption of the negatively charged bacterial membrane.
Why it’s plausible
Plasticins are a subfamily of frog skin AMPs (amphibian antimicrobial peptides) whose founding members (plasticins from Xenopus laevis relatives) have documented antibacterial activity. The sequence name 'Plasticin-S1' places this peptide in that family lineage. Bacterial outer membranes carry net negative charge from lipopolysaccharide and phosphatidylglycerol, attracting cationic amphipathic peptides in the same way PS-exposing cancer cells do. The C-terminal KKI terminus and the hydrophobic DLLSTVTGLL segment satisfy both the charge-attraction and membrane-insertion requirements for antibacterial lysis. Gram-positive bacteria (MRSA, VRE) lack an outer membrane barrier, making the peptide's amphipathic helix directly accessible to the cytoplasmic membrane. The anticancer annotation likely underrepresents the full activity spectrum given the family classification.
Why it matters
If Plasticin-S1 kills both drug-resistant bacteria and cancer cells, it becomes a dual-indication candidate at a time when the antibiotic pipeline is critically depleted. Demonstrating dual activity on the same mechanistic basis would allow shared preclinical studies (toxicology, pharmacokinetics) to inform both indications simultaneously, reducing development cost.
Plausibility.64
Novelty.33
Impact.63
Basis · grounding2 papers · 1 computed/note
[1]
sequencePeptide name 'Plasticin-S1' places it in the plasticin subfamily of amphibian skin AMPs, whose characterized members include antibacterial peptides from frog skin secretions.
[2]
paper
Membrane composition-driven selectivity for cancer cells is described; bacteria share anionic surface charge with cancer cells, predicting cross-activity for charge-driven lytic peptides.
doi: 10.1371/journal.pone.0162007
[3]
paper
Review covers anticancer peptide mechanisms including membrane disruption; the same lytic mechanism is operative in classic AMPs against bacteria, supporting the repurposing hypothesis.
doi: 10.1016/j.cbi.2022.110194
openupdated 2026-06-05

Could this peptide kill cancer cells by punching through their surface, rather than by latching onto a specific target?

Most targeted cancer drugs stop working when tumors mutate the molecular target they aim at. A therapy that kills by disrupting the membrane itself is much harder to escape through mutation. If this mechanism is confirmed, it could mean Plasticin-S1 stays effective across a broad range of cancer types without needing genetic testing to find the right patients.

The hypothesis
The hydrophobic C-terminal segment GLVSDLLSTVTGLLGNLGGGGLKKI of Plasticin-S1 inserts into and disrupts the negatively charged outer leaflet of cancer cell membranes independently of a protein receptor, killing cells through membrane lysis rather than through receptor-mediated signaling.
Why it’s plausible
The sequence has a clear bipartite structure: an N-terminal acidic/charged tract (EEEKREGENEKEQEDDNQSEEK) and a C-terminal amphipathic hydrophobic segment (GLVSDLLSTVTGLLGNLGGGGLKKI) ending in KKI. The C-terminal region contains a pattern (DLLSTVTGLL, GNLGGGGL) that could adopt an amphipathic helix or beta-strand with a hydrophobic face suitable for membrane insertion. Cancer cells overexpress phosphatidylserine on their outer leaflet, providing electrostatic complementarity for the cationic KKI terminus. The glycine-rich GGGGL motif lowers helical rigidity, promoting the conformational flexibility needed for membrane pore formation. The dermaseptin-PS1 family, referenced in the axis hits, uses an analogous membrane-lytic mechanism.
Why it matters
If the anticancer activity is membrane-lytic and receptor-independent, resistance through target mutation is unlikely, making Plasticin-S1 intrinsically more durable than targeted therapies. It also means activity will correlate with membrane composition rather than genomic subtype, opening a route to biomarker-free broad-spectrum cancer cell killing.
Plausibility.72
Novelty.17
Impact.68
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC-terminal segment GLVSDLLSTVTGLLGNLGGGGLKKI contains alternating hydrophobic/polar residues and terminal KKI, consistent with amphipathic membrane-active peptides.
[2]
paper
Dermaseptin-PS1, a related plasticin-family peptide, exhibits anticancer activity via intrinsic apoptosis signaling, implicating membrane disruption upstream of apoptosis.
doi: 10.1111/jcmm.14032
[3]
paper
Anticancer peptides with high cancer-cell selectivity are described as acting directly on the cell membrane, reducing resistance mechanisms.
doi: 10.1371/journal.pone.0162007
openupdated 2026-06-05

Could this peptide tell cancer cells apart from healthy ones, and attack only the cancer?

One of the biggest challenges with cancer treatment is avoiding harm to healthy tissue. Cancer cells commonly display a specific fat molecule on their outer surface that most normal cells keep hidden inside. If Plasticin-S1 is activated by that signal, it could kill cancer cells while leaving healthy ones largely alone, potentially meaning fewer side effects for patients.

The hypothesis
Plasticin-S1 is selectively cytotoxic to cancer cells over normal cells because its lytic C-terminal segment is activated preferentially by the elevated phosphatidylserine exposure and hyperpolarized surface charge found on tumor cell membranes, and it remains inert toward normal cells whose outer leaflet is dominated by phosphatidylcholine and sphingomyelin.
Why it’s plausible
Phosphatidylserine is constitutively exposed on the outer leaflet of many cancer cell types at levels 3-7 times higher than in normal cells, creating a negatively charged surface that attracts cationic amphipathic peptides. The terminal KKI motif of Plasticin-S1 provides a positively charged anchor that would concentrate the peptide at PS-rich surfaces. Normal cell membranes present a near-neutral outer leaflet that would not provide sufficient electrostatic attraction to trigger membrane insertion at physiological peptide concentrations. This is consistent with the broader axis-hit literature characterizing high cancer-cell selectivity for membrane-active peptides.
Why it matters
If selectivity is PS-driven, it creates a direct bridge to the tumor vasculature targeting field, where PS-binding peptides are already in clinical use. Plasticin-S1 could serve as a scaffold for tumor-homing agents, and its therapeutic window could be quantitatively predicted from PS-exposure levels on a cancer-by-cancer basis.
Plausibility.53
Novelty.17
Impact.62
Basis · grounding2 papers · 1 computed/note
[1]
paper
Anticancer peptides with high cancer-cell selectivity are described as interacting directly with the cell membrane; selective killing attributed to differences in membrane composition between cancer and normal cells.
doi: 10.1371/journal.pone.0162007
[2]
sequenceC-terminal KKI provides cationic anchor; DLLSTVTGLL provides hydrophobic insertion element; together they match the charge-attraction/hydrophobic-insertion two-step model of PS-selective lysis.
[3]
paper
Review of anticancer peptide mechanisms discusses membrane composition-driven selectivity as a primary determinant of cancer vs. normal cell discrimination.
doi: 10.1016/j.cbi.2022.110194
details expand to inspect
full evidence table1 metrics
metricvaluetool
ranking score 0.612529456615448 boltz-2
3-letter notation
Glu-Glu-Glu-Lys-Arg-Glu-Gly-Glu-Asn-Glu-Lys-Glu-Gln-Glu-Asp-Asp-Asn-Gln-Ser-Glu-Glu-Lys-Arg-Gly-Leu-Val-Ser-Asp-Leu-Leu-Ser-Thr-Val-Thr-Gly-Leu-Leu-Gly-Asn-Leu-Gly-Gly-Gly-Gly-Leu-Lys-Lys-Ile
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). Plasticin-S1 anticancer peptide (pep-05356, v1). PeptideModel. https://peptidemodel.com/card/pep-05356
@peptide{pep05356,
  sequence = {EEEKREGENEKEQEDDNQSEEKRGLVSDLLSTVTGLLGNLGGGGLKKI},
  target   = {anticancer},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 5 by signal overlap
references 3 papers
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