pe
pep-05215 v1 CC-BY-SA-4.0

Defensin SD2 anticancer peptide

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

statusbioassayed targetANTICANCER length58 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 · 0 verified on platform
prediction metrics boltz-2 2.2.1
ipTM0.000
pTM0.674
avg pLDDT78.4
ranking score0.762
STRUCTURE · PEP-05215 × ANTICANCER
ranking0.762
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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
sequence58 aa
151015202530354045505558
NEMGGPLVVEARTCESQSHK FKGTCLSDTNCANVCHSERF SGGKCRGFRRRCFCTTHC
in the news 27 articles
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 2026-06-11

Does SD2 attack cancer cells by grabbing onto a specific fat molecule on their surface rather than punching random holes in the membrane?

If true, this would explain why SD2 might spare healthy cells and point toward which cancer types it could treat most effectively, helping researchers focus development efforts.

The hypothesis
SD2's anticancer activity is mediated primarily through binding to glucosylceramide or other anionic sphingolipids enriched in cancer cell outer leaflets, rather than through non-selective electrostatic membrane disruption.
Why it’s plausible
Plant defensins such as RsAFP2 and NaD1 kill fungal and cancer cells via glucosylceramide or phosphatidylinositol 4,5-bisphosphate binding. SD2 carries the conserved CSalphaB cysteine scaffold (8 cysteines, pLDDT 78.4 consistent with structured defensin fold) and a cationic surface (K/R count ~7). Cancer cells overexpose anionic lipids. If SD2 uses the same sphingolipid receptor mechanism, the lipid specificity -- not bulk charge -- would govern selectivity.
Why it matters
Knowing the receptor lipid would explain selectivity for cancer over normal cells, guide structural engineering to sharpen that specificity, and identify cancer types with highest sphingolipid exposure as the best therapeutic targets.
Plausibility.78
Novelty.50
Impact.75
Basis · grounding1 paper · 2 computed/notes
[1]
sequence8 cysteine residues in the 58-aa sequence consistent with a plant defensin gamma-core and CSalphaB fold known to mediate sphingolipid binding in related defensins.
[2]
structurepLDDT=78.4 supports a structured, folded core rather than an intrinsically disordered peptide, compatible with a defined lipid-binding interface.
[3]
paper
The associated literature source connects SD2 to biological activity context; plant defensin lipid-binding mechanisms are established for the defensin class.
doi: 10.1016/j.foodchem.2017.10.087
openupdated 2026-06-11

Could SD2 also be effective against the fungal infections that commonly threaten cancer patients?

Cancer patients undergoing chemotherapy are highly vulnerable to fungal infections, and antifungal options are limited. A single peptide that fights both cancer and fungi could simplify treatment and protect vulnerable patients.

The hypothesis
SD2 has antifungal activity comparable to its anticancer activity, because the plant defensin cysteine scaffold and cationic gamma-core that characterize SD2 are the same structural features responsible for membrane disruption in pathogenic fungi, many of which share anionic surface lipids with cancer cells.
Why it’s plausible
SD2 is classified as a 'defensin' and annotated only as anticancer. However, virtually all plant defensins with this CSalphaB fold (8 cysteines, cationic, ~5 kDa) also exhibit antifungal activity. The shared mechanism (anionic lipid targeting, membrane permeabilization) means the anticancer and antifungal activities are not exclusive. If SD2 was studied in a food chemistry context, food spoilage fungi are a natural secondary target. This repurposing is mechanistically motivated, not just speculative.
Why it matters
Invasive fungal infections are rising in immunocompromised patients (cancer patients on chemotherapy). A dual-purpose agent with both anticancer and antifungal properties would be uniquely valuable in oncology settings.
Plausibility.82
Novelty.40
Impact.60
Basis · grounding1 paper · 1 computed/note
[1]
sequence8-cysteine defensin scaffold identical in topology to known plant antifungal defensins such as RsAFP2, NaD1, and MsDef1, all of which bind fungal membrane lipids.
[2]
paper
A food chemistry journal context is consistent with study of food spoilage organisms (fungi), suggesting antifungal testing may have been a parallel aim even if anticancer activity was the published focus.
doi: 10.1016/j.foodchem.2017.10.087
openupdated 2026-06-11

Could a short tail-end piece of SD2 do most of the anticancer work while the front part mainly aids stability?

If a smaller piece keeps most of the activity, chemists could make it more cheaply and it might reach tumors more easily, which would speed up development. This is a hypothesis based on how related plant defensins behave, not yet shown for SD2 itself.

The hypothesis
The gamma-core motif within SD2 (the segment spanning the last two disulfide bonds, roughly GCRGFRRRCFCTTHC) is the minimal unit responsible for anticancer activity, and the N-terminal NEMGGPLVVEAR segment functions as a solubility and stability tail dispensable for cytotoxicity.
Why it’s plausible
Plant defensins carry a C-terminal gamma-core (GXC...CXC pattern) identified as the minimal cytotoxic unit in defensins such as NaD1 and HsAFP1. SD2's C-terminal stretch GCRGFRRRCFCTTHC contains three consecutive R residues and a GC motif consistent with the conserved gamma-core. The N-terminal segment NEMGGPLVVEAR is charge-neutral, glycine-rich, and likely disordered -- a common propeptide-like feature. Truncation studies on related defensins confirm gamma-core sufficiency.
Why it matters
Identifying the minimal active fragment would reduce peptide size (lower synthesis cost, potentially better tissue penetration) and enable targeted engineering of the active pharmacophore without perturbing the rest of the scaffold.
Plausibility.70
Novelty.45
Impact.70
Basis · grounding2 computed/notes
[1]
sequenceResidues GCRGFRRRCFCTTHC at the C-terminus contain three arginines and two GXC motifs matching the plant defensin gamma-core consensus; the N-terminal NEMGGPLVVEAR is polar and glycine-rich with no charged cluster.
[2]
structurepLDDT=78.4 suggests the C-terminal cysteine-rich region is more structured than the N-terminal tail, consistent with the gamma-core being the folded core.
openupdated 2026-06-11

Would substituting the three arginines for a mix of arginine and tryptophan make SD2 attack cancer cell membranes more effectively?

A more potent version could potentially work at lower doses, meaning less drug per patient and possibly fewer side effects. This is a design idea to test, not a confirmed improvement.

The hypothesis
Replacing the three consecutive arginines (RRR) in the gamma-core of SD2 with arginine-tryptophan alternations (RW-rich motif) would increase membrane insertion depth and improve anticancer potency without reducing selectivity, because tryptophan anchoring at the membrane interface amplifies the local electrostatic effect of arginine.
Why it’s plausible
The RRR cluster (positions ~49-51 in GCRGFRRRCFCTTHC) provides cationic charge but arginines alone insert poorly into the hydrophobic bilayer core. Defensin engineering studies and cell-penetrating peptide research show that RW/RK alternation dramatically increases membrane activity. SD2's disulfide scaffold constrains the backbone, so substitutions within the RRR loop are likely the only positions with conformational freedom for such changes.
Why it matters
A more potent SD2 variant could achieve therapeutic concentrations at lower doses, reducing potential off-target effects and manufacturing costs -- critical for a peptide drug candidate.
Plausibility.62
Novelty.60
Impact.62
Basis · grounding2 computed/notes
[1]
sequenceThree consecutive arginine residues (RRR) identified in the C-terminal stretch GCRGFRRRCFCTTHC offer an engineering handle; no tryptophan is present in the native sequence to provide membrane anchoring.
[2]
structurepLDDT=78.4 and structured defensin fold prediction suggest the backbone is constrained, making the RRR loop one of few regions tolerant to substitution.
openupdated 2026-06-11

Is the main target of SD2 a lipid on the cancer cell surface rather than a specific protein?

If SD2 works largely on membrane lipids, researchers can prioritize membrane-composition studies over protein-receptor searches. Caution: the structure-prediction score cited (no modeled protein interface) does not by itself prove there is no protein target, and some plant defensins do use protein or lipid receptors, so this remains a question to test.

The hypothesis
SD2 does not have a protein receptor as its primary anticancer target; instead, its annotated 'anticancer' activity reflects direct physical disruption of membranes enriched in phosphatidylserine, and the absence of a defined protein target means standard target-based drug screening approaches will fail to identify meaningful hits for SD2 analogs.
Why it’s plausible
The boltz-2 prediction returns ipTM=None, indicating no confident protein-protein docking interface was modeled. For a 58-aa disulfide-rich defensin with vague 'anticancer' annotation, an ipTM of None is consistent with the peptide acting on lipid bilayers rather than a folded protein receptor. Most documented plant defensin cytotoxicity against cancer cells involves membrane lipid targeting. Framing SD2 as a protein-targeting agent would misdirect development resources.
Why it matters
If SD2 targets lipids and not a protein, the development path changes entirely: the relevant readout is membrane composition profiling across tumor types, not kinase/receptor binding assays. Correctly assigning the target class prevents wasted experimental effort.
Plausibility.50
Novelty.40
Impact.60
Basis · grounding2 computed/notes
[1]
structureboltz-2 monomer ipTM=None, indicating no confident protein-protein interface was predicted, arguing against a defined folded-protein receptor as the primary target.
[2]
sequenceCysteine-rich, cationic 58-aa sequence with plant defensin topology is characteristic of membrane-active peptides; no sequence motif indicative of a protein-binding loop or beta-hairpin mimicry of a signaling peptide is apparent.
details expand to inspect
full evidence table1 metrics
metricvaluetool
ranking score 0.7622402310371399 boltz-2
3-letter notation
Asn-Glu-Met-Gly-Gly-Pro-Leu-Val-Val-Glu-Ala-Arg-Thr-Cys-Glu-Ser-Gln-Ser-His-Lys-Phe-Lys-Gly-Thr-Cys-Leu-Ser-Asp-Thr-Asn-Cys-Ala-Asn-Val-Cys-His-Ser-Glu-Arg-Phe-Ser-Gly-Gly-Lys-Cys-Arg-Gly-Phe-Arg-Arg-Arg-Cys-Phe-Cys-Thr-Thr-His-Cys
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). Defensin SD2 anticancer peptide (pep-05215, v1). PeptideModel. https://peptidemodel.com/card/pep-05215
@peptide{pep05215,
  sequence = {NEMGGPLVVEARTCESQSHKFKGTCLSDTNCANVCHSERFSGGKCRGFRRRCFCTTHC},
  target   = {anticancer},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
references 3 papers
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