status 2 / 5 · 0 verified on platform

prediction metrics boltz-2 2.2.1

ipTM0.000

pTM0.493

avg pLDDT61.4

ranking score0.590

in the news 27 articles

Most cancer-vaccine peptides do nothing. A 352-patient dataset says why. ANTICANCER IMMUNE · via ANTICANCER

@pavel · 2d ago

A KRAS cancer vaccine missed its trial. The groups weren't even. ANTICANCER · via ANTICANCER

@pavel · 3d ago

A peptide vaccine kept most kids with refractory leukemia alive after transplant ANTICANCER IMMUNE · via ANTICANCER

@pavel · 9d ago

Hypotheses3 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 trimming a useless chunk off a natural frog peptide and replacing it with a tumor-homing tag make it far better at killing cancer cells without harming healthy ones?

If this engineering step works, it could turn a weak, unfocused peptide into one that homes to tumors and attacks them at a much lower dose, which would matter for people with solid cancers and for researchers trying to shrink both the cost and side effects of peptide-based therapies.

The hypothesis

Truncating or replacing the anionic N-terminal domain of Dermaseptin-S11 with a short tumor-targeting ligand (such as an RGD or NGR sequence) while retaining the RALWKTLLKGAGKVFGHVAKQFLGSQGQPES C-terminal core will produce an analog with at least 10-fold higher potency and maintained or improved selectivity for integrin-overexpressing solid tumors.

Why it’s plausible

The C-terminal core of Dermaseptin-S11 (residues 23-53) structurally matches the membrane-active domain seen in dermaseptins S9 and PS1, both of which show antiproliferative activity. The long anionic N-terminus (22 residues out of 53) currently constitutes nearly 40% of the peptide's mass. Replacing it with a compact integrin-binding sequence would retain the membrane-lytic warhead while redirecting activity to alpha-v/beta-3 or alpha-5/beta-1 integrins upregulated on tumor vasculature and many solid tumor cells. Dermaseptin B2 was noted for antitumor and angiostatic activity; a short RGD-fused analog of the S11 core could combine direct cancer cell lysis with vascular targeting. The manufacturing axis hit explicitly notes SPPS length limits at ~50 amino acids, so removing 22 residues from the N-terminus would improve manufacturability simultaneously.

Why it matters

Engineering a tumor-targeted Dermaseptin-S11 core by replacing the non-canonical anionic N-terminus with a targeting motif would convert a poorly understood parent peptide into a rationally designed cancer-selective agent, directly addressing potency, selectivity, and manufacturing cost in a single modification.

Plausibility.68

Novelty.47

Impact.77

Basis · grounding3 papers · 1 computed/note

[1]

sequenceResidues 23-53 (RALWKTLLKGAGKVFGHVAKQFLGSQGQPES, 31 residues) constitute the putative amphipathic core; removing residues 1-22 would yield a peptide well within SPPS length limits.

[2]

paper

Dermaseptin DMS-PS2 showed efficacy in MRSA-infected wound healing in vivo, establishing that dermaseptin C-terminal cores retain biological activity in truncated or analog forms.

doi: 10.1016/j.actbio.2020.03.024

[3]

paper

Dermaseptin S4 (1-16) identified as a candidate for modification via substitution to enhance selectivity, establishing precedent for N-terminal domain engineering in this family.

doi: 10.1016/j.vaccine.2018.01.066

[4]

paper

SPPS length limitation of ~50 amino acids noted as a manufacturing constraint; reducing peptide length from 53 to ~33 residues would remove this limitation.

doi: 10.1038/s41467-023-37003-z

openupdated 2026-06-05

Could the charged tail of this peptide act like a safety lock, keeping it harmless in healthy tissue and only releasing its cell-killing ability in the acidic conditions found inside tumors?

If true, the peptide would behave like a built-in smart drug that activates only where it is needed, potentially reducing damage to healthy tissue, which is one of the biggest unsolved problems with existing cancer-killing peptides.

The hypothesis

The unusually long anionic N-terminal domain (EEEKRENEDEEEQEDDEQ, approximately residues 1-18) of Dermaseptin-S11 acts as an autoinhibitory electrostatic clamp that suppresses membrane insertion of the C-terminal amphipathic helix at physiological pH, and the peptide becomes membrane-active only upon local acidification such as occurs in tumor microenvironments or endosomes.

Why it’s plausible

Classical dermaseptins are cationic and rely on electrostatic attraction to anionic bacterial or cancer cell membranes. Dermaseptin-S11's sequence is strikingly bipartite: the first ~18 residues contain six glutamate/aspartate residues plus glutamine repeats, giving a strongly negative charge, whereas residues 23-53 carry the conserved LWKTLLK/VFGH motif characteristic of membrane-active dermaseptins. The anionic tail could fold back onto or electrostatically shield the cationic helix at neutral pH. The low average pLDDT (61.4) and low ptm (0.49) from the Boltz-2 structure prediction are consistent with a disordered N-terminal tail that lacks a fixed conformation, a feature often seen in pH-sensitive autoinhibited peptides. At tumor-microenvironment pH (~6.5-6.8), protonation of Asp/Glu residues would reduce repulsion and allow the C-terminal helix to insert. This mechanism would explain selective toxicity to solid tumors over normal tissue.

Why it matters

If the anionic tail confers tumor-pH-selective activation, Dermaseptin-S11 would represent a self-regulating prodrug-like peptide with built-in selectivity for solid tumors, distinguishing it from non-selective membrane-lytic dermaseptins and directly addressing the canonical selectivity problem noted across the dermaseptin literature.

Plausibility.52

Novelty.65

Impact.78

Basis · grounding2 papers · 2 computed/notes

[1]

sequenceResidues 1-18 contain EEEKRENEDEEEQEDDEQ: six Glu/Asp, strongly anionic; residues 23-53 contain RALWKTLLKGAGKVFGHVAKQFLGS, the cationic amphipathic core.

[2]

structureavg_plddt 61.4 and ptm 0.49 indicate the monomer is partially disordered, consistent with a floppy anionic tail that does not adopt a fixed helix.

[3]

paper

Electrostatic interaction between cationic antimicrobial peptides and anionic cancer cell membranes is the dominant perception for selectivity; Dermaseptin-S11's reversed N-terminal charge is anomalous and unexplained.

doi: 10.1007/s11356-021-13683-2

[4]

paper

Peptide aggregation in solution driven by hydrophobic N-terminal sequences of dermaseptin S4 strongly affects cytotoxic potency, showing that sequence context upstream of the core helix controls activity.

doi: 10.1074/jbc.275.6.4230

openupdated 2026-06-05

Could this peptide tell cancer cells apart from normal ones by latching onto a fat molecule that cancer cells display on their surface but healthy red blood cells keep tucked away inside?

If the selectivity mechanism holds up, it would explain how to design safer peptide therapies that kill tumors without destroying red blood cells, addressing a key safety problem that has held back this entire class of compounds.

The hypothesis

Dermaseptin-S11 displays preferential cytotoxicity toward phosphatidylserine-rich cancer cell membranes over normal cells because its cationic amphipathic C-terminal helix (RALWKTLLKGAGKVFGHVAKQFLGS) binds externalized phosphatidylserine with higher affinity than phosphatidylcholine, while the anionic N-terminal tail reduces non-specific binding to healthy erythrocytes.

Why it’s plausible

Externalized phosphatidylserine is a well-established marker of apoptotic and cancer cells. The LWKTLLK segment contains a tryptophan and two lysines in a geometry compatible with phosphatidylserine head-group coordination. The flanking anionic N-terminus would electrostatically repel healthy erythrocytes (which expose phosphatidylcholine and sphingomyelin outward). Dermaseptin B2 was shown to have antitumor and angiostatic activity against prostate and mammary cancers, and the selectivity axis hit literature directly discusses how cationic dermaseptins exploit anionic cancer membranes. Dermaseptin-S11's unusual charge distribution could extend this selectivity further by adding repulsion at normal membranes.

Why it matters

Demonstrating that Dermaseptin-S11 achieves cancer selectivity through a combined cationic-core plus anionic-tail mechanism would provide a structural rationale for engineering safer dermaseptin analogs with minimized hemolysis, a major bottleneck noted in multiple dermaseptin structure-activity studies.

Plausibility.53

Novelty.35

Impact.60

Basis · grounding3 papers · 1 computed/note

[1]

paper

Dermaseptins B2 and B3 are active against prostate, mammary, and lymphoma cells; cancer cell selectivity linked to anionic membrane composition.

doi: 10.3390/toxins8050144

[2]

paper

Cytotoxic selectivity and mechanism are still hard to identify across dermaseptins; cellular selectivity remains an open problem.

doi: 10.1007/s11356-021-13683-2

[3]

paper

Dermaseptin S1 selected for structure-activity study because of its lowest hemolytic activity among the family, indicating hemolysis is a primary concern.

doi: 10.1016/j.bmc.2008.07.032

[4]

sequenceLWKTLLK motif at positions 25-31 provides two Lys plus Trp in an arrangement suited for membrane targeting via electrostatic and hydrophobic contacts.

details expand to inspect

▸full evidence table1 metrics

metric	value	tool
ranking score	0.5897356271743774	boltz-2

▸3-letter notation

Glu-Glu-Glu-Lys-Arg-Glu-Asn-Glu-Asp-Glu-Glu-Glu-Gln-Glu-Asp-Asp-Glu-Gln-Ser-Glu-Glu-Lys-Arg-Ala-Leu-Trp-Lys-Thr-Leu-Leu-Lys-Gly-Ala-Gly-Lys-Val-Phe-Gly-His-Val-Ala-Lys-Gln-Phe-Leu-Gly-Ser-Gln-Gly-Gln-Pro-Glu-Ser

▸recipeboltz-2 2.2.1

parameter	value
model	boltz-2 2.2.1
weights	—
hardware	vast_v100_32gb
mlx version	—
python	—
random seed	1
msa strategy	none_monomer
runtime	—
predicted by	—
predicted at	2026-05-23

▸citationbibtex

peptidemodel (2026). Dermaseptin-S11 anticancer peptide (pep-05261, v1). PeptideModel. https://peptidemodel.com/card/pep-05261

@peptide{pep05261,
  sequence = {EEEKRENEDEEEQEDDEQSEEKRALWKTLLKGAGKVFGHVAKQFLGSQGQPES},
  target   = {anticancer},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}

related peptides 4 by signal overlap

pep-05288 Dermaseptin anticancer peptide same target ·3 shared papers

pep-05289 Dermaseptin cancer-fighting peptide same target ·3 shared papers

pep-05378 Cationic antimicrobial protein anticancer pepti… same target ·3 shared papers

pep-05356 Plasticin-S1 anticancer peptide same target ·2 shared papers

references 7 papers

[1]

Novel dermaseptin, adenoregulin and caerin homologs from the Central American red-eyed leaf frog, Agalychnis callidryas, revealed by functional peptidomics of defensive skin secretion

Wang, L. et al. Biochimie 2008

doi: 10.1016/j.biochi.2008.04.016

supporting

[2]