pe
pep-05657 v1 CC-BY-SA-4.0

Palustrin-2CG1 germ-killing peptide

A short protein fragment that kills or slows the growth of bacteria or other microbes; used only as a lab research tool.

statuscomputed targetANTIMICROBIAL length55 aa refs3
antimicrobial
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
pTM0.405
avg pLDDT66.0
ranking score0.609
STRUCTURE · PEP-05657 × ANTIMICROBIAL
ranking0.609
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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
sequence55 aa
1510152025303540455055
GTISSLCEQER DANEDEVLEEV KRGIWDSIKTF GKKFALNIMDK IKCKIGGGCPP
in the news 6 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

Is there a natural peptide that attacks cancer cells but ignores healthy ones because of a built-in charge filter?

Cancer cells have an unusual electrical charge on their outer surface that healthy cells lack. If this hypothesis holds, palustrin-2CG1 could selectively kill melanoma and leukemia cells while leaving normal blood cells untouched, pointing toward a new class of targeted anticancer drugs for people who need treatments with fewer side effects.

The hypothesis
Palustrin-2CG1 exerts selective cytotoxic activity against cancer cell lines with elevated phosphatidylserine exposure on the outer membrane leaflet (e.g., certain melanoma and leukemia lines) at concentrations that spare normal erythrocytes and peripheral blood mononuclear cells, because the anionic N-terminal segment (EQERDANEDEVLEE, residues 3-18) partially masks activity against neutral-outer-leaflet membranes while still allowing the cationic core to engage highly negative cancer-cell surfaces.
Why it’s plausible
The literature chunk from 10.1177/0022034516679973 explicitly states that cancer cells lose membrane asymmetry, making their outer leaflet more negatively charged, which explains why cationic AMPs can preferentially lyse cancer cells. Palustrin-2CG1 is unusual among AMPs in having a substantially anionic N-terminal domain that would reduce total net charge at neutral pH; this internal charge balance could raise the effective threshold of membrane negativity required for activity, thereby providing a built-in selectivity filter that selects for cancer cells over normal cells.
Why it matters
If palustrin-2CG1 has a selectivity window for cancer cells arising from its unusual charge distribution, it becomes a candidate anticancer peptide rather than solely an antibiotic, substantially expanding its therapeutic scope.
Plausibility.50
Novelty.67
Impact.70
Basis · grounding2 papers · 1 computed/note
[1]
sequenceN-terminal region contains E5, E9, D10, E14, D15, E16, E17 (predominantly anionic), partially offsetting cationic K/R residues in the C-terminal half.
[2]
paper
Cancer cells lose membrane asymmetry, making their outer surface more negatively charged; some cationic AMPs exploit this for selective cytotoxicity.
doi: 10.1177/0022034516679973
[3]
paper
Palustrin-2 family peptides show broad-spectrum antimicrobial activity and low hemolysis, suggesting an existing selectivity margin that could extend to cancer cell membranes.
doi: 10.3390/antibiotics11081048
openupdated 2026-06-05

Could swapping one amino acid turn a manufacturing headache into a stable, high-yield drug candidate?

Long peptide drugs often tangle and degrade during production, driving up costs and limiting shelf life. If this single substitution works as predicted, it could raise manufacturing yields and extend how long the peptide survives in the body, making it more practical to develop as an actual medicine for patients with drug-resistant infections.

The hypothesis
A palustrin-2CG1 analogue in which the C8 cysteine is replaced with serine and the C46-C50 disulfide is retained as a monocyclic peptide will show greater proteolytic stability than the linear form because the cyclic Rana box sterically occludes C-terminal exopeptidase access, while the freed C8 prevents aberrant intermolecular disulfide scrambling that would otherwise reduce yield and increase aggregation during SPPS of the 55-residue chain.
Why it’s plausible
Three cysteines at positions 8, 46, and 50 create a potential for mis-pairing: the C8 residue is remote from the canonical C46-C50 Rana box ring and its free thiol could form spurious intermolecular disulfides. Replacing C8 with serine (conservative, maintaining the hydroxyl) isolates the Rana box as the sole disulfide, simplifying folding and reducing aggregation. The cyclic Rana box at the C-terminus is known from other palustrin-2 members to be stable and resistant to carboxypeptidases.
Why it matters
This single substitution could substantially improve the manufacturing yield and plasma half-life of palustrin-2CG1, directly addressing two of the major cost and stability barriers flagged in the manufacturing and proteolytic-stability axis hits.
Plausibility.47
Novelty.47
Impact.62
Basis · grounding3 papers · 1 computed/note
[1]
sequenceThree cysteines at C8, C46, C50; C46-C50 forms the Rana box ring; C8 is isolated and could form non-native disulfides.
[2]
paper
Disulfide bridge structure-activity studies on palustrin-2ISb show the Rana box is retained in active analogues; modification of disulfide pairing is a validated engineering strategy in this family.
doi: 10.3390/antibiotics11081048
[3]
paper
Proteolytic degradation is a significant elimination pathway for therapeutic peptides; structural constraints including cyclic motifs can improve stability.
doi: 10.3389/fphar.2026.1778569
[4]
paper
SPPS length limit (~50 aa) and aggregation are production barriers for AMPs of this size; reducing cysteine count simplifies synthesis.
doi: 10.1038/s41467-023-37003-z
openupdated 2026-06-05

Does this peptide tear bacterial membranes apart like a detergent, or does it poke precise holes, and why does that matter?

The way an antibiotic kills bacteria determines which resistance tricks bacteria can use against it. If palustrin-2CG1 works by smothering the bacterial surface rather than forming fixed channels, resistance would be much harder for bacteria to evolve, and the active region could potentially be shortened into a smaller, cheaper drug for people with resistant infections.

The hypothesis
Palustrin-2CG1 disrupts bacterial membranes via a carpet or toroidal-pore mechanism driven by an amphipathic helix formed by residues ~28-45 (IWDSIKTFGKKFALNIMD), not through a barrel-stave channel, because this region carries both a dense cationic patch (K38, K39, K44) and a contiguous hydrophobic face but lacks the heptad repeat periodicity required for stable transmembrane helical bundles.
Why it’s plausible
Inspection of the sequence reveals a central amphipathic segment (IWDSIKTFGKKFALNIMD) with alternating hydrophobic and cationic residues consistent with an amphipathic helix that lies flat on the membrane surface and disrupts it through mass-action rather than inserted channels. The N-terminal region (GTISSLCEQERDANEDEVLEE) is predominantly anionic and likely remains disordered at the membrane surface, concentrating cationic disruption to the central-C-terminal half. The low avg_plddt (66.05) corroborates a peptide that is largely unstructured in solution and folds only upon membrane contact, a hallmark of carpet-model AMPs.
Why it matters
Distinguishing the disruption mode determines whether the peptide can be truncated to the active helix without losing potency, and whether resistance via membrane remodeling versus efflux pumps is the more likely obstacle in clinical development.
Plausibility.57
Novelty.28
Impact.57
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceResidues 28-45 (IWDSIKTFGKKFALNIMD) contain a hydrophobic face (I28, W29, F36, A37, L38-ish, I43, M44) and a cationic face (K32, K38, K39, K44), consistent with an amphipathic helix.
[2]
structureavg_plddt 66.05 indicates the monomer is largely disordered in isolation, consistent with membrane-induced folding.
[3]
paper
Cationic AMPs adopt amphipathic conformations upon interaction with negatively charged bacterial membranes; carpet and toroidal models are the dominant mechanisms for this structural class.
doi: 10.1177/0022034516679973
openupdated 2026-06-05

Does this peptide get captured by proteins in the blood before it can do its job?

Many promising antibiotics look great in lab tests but underperform in the body because blood proteins intercept them. If this hypothesis is confirmed, small tweaks to the peptide's charged end could prevent that interception, potentially turning a lab curiosity into a drug that actually works at lower doses in patients with systemic infections.

The hypothesis
The anionic N-terminal segment of palustrin-2CG1 (residues 3-18, ISSLCEQERDANEDEVL) engages host-defense pattern recognition co-receptors (e.g., CD14 or LPS-binding protein) or serum proteins through electrostatic and hydrogen-bond contacts, reducing effective free peptide concentration in plasma and partially explaining the high MIC values sometimes observed for palustrin-2 family peptides in serum-containing media relative to buffer.
Why it’s plausible
Most palustrin-2 family AMPs show serum-sensitivity, meaning MICs rise substantially in the presence of serum. The long anionic N-terminal domain of palustrin-2CG1 is atypical for an AMP and resembles the charge profile of acidic serum proteins that interact with cationic host defense receptors. Sequestration by serum proteins is a well-documented limitation for cationic AMPs (10.1038/s41573-019-0058-8), but a peptide with its own anionic domain might also interact with anionic serum proteins in a self-inhibitory manner at the N-terminus.
Why it matters
If N-terminal serum binding is confirmed, targeted mutagenesis of the anionic residues (e.g., E-to-Q or E-to-A substitutions) could dramatically improve serum stability and reduce effective MIC in vivo without disrupting the membrane-active core.
Plausibility.40
Novelty.55
Impact.57
Basis · grounding2 papers · 1 computed/note
[1]
sequenceResidues 3-18 are predominantly anionic (E, D content), which is unusual for a membrane-disrupting AMP and suggests a domain with a distinct binding function.
[2]
paper
Serum proteins sequester cationic host defense peptides, a major barrier to clinical translation; palustrin-2 family serum sensitivity is implied by MIC comparisons in the axis hits.
doi: 10.1038/s41573-019-0058-8
[3]
paper
MIC data for palustrin-2ISa, -2ISb and analogues are reported; context implies assay conditions relevant to serum effects.
doi: 10.1016/j.peptides.2011.08.024
openupdated 2026-06-05

Could palustrin-2CG1 tackle the stubborn fungal films that form on catheters and implants and resist standard drugs?

Candida biofilms on medical devices cause life-threatening infections in hospital patients, and existing antifungals often fail against them. If this peptide disrupts those biofilms through a different mechanism than current drugs, it could work alongside azole antifungals to treat infections that are currently very difficult to clear, especially in immunocompromised patients.

The hypothesis
Palustrin-2CG1 disrupts Candida albicans biofilm formation at sub-MIC concentrations by intercalating into the fungal cell membrane (ergosterol-containing, negatively charged relative to mammalian membranes) via its amphipathic core, making it effective against drug-resistant candidiasis in a way that is additive or synergistic with azole antifungals.
Why it’s plausible
Frog-skin AMPs of the palustrin family have documented broad-spectrum activity that includes fungal targets, as indicated by the GL-29 data reporting activity against C. albicans. Biofilm-associated Candida infections are a major unmet clinical need, particularly in immunocompromised and catheter patients. Palustrin-2CG1's amphipathic core would interact with ergosterol-containing fungal membranes through a mechanism distinct from azole inhibition of ergosterol biosynthesis, suggesting mechanistic orthogonality and potential synergy. The low hemolysis of the family is important because anti-Candida therapy often requires systemic dosing.
Why it matters
Repositioning palustrin-2CG1 as an anti-biofilm agent against Candida would address a serious gap in antifungal armamentarium and leverage the known broad-spectrum profile of the palustrin family beyond its antibacterial classification.
Plausibility.42
Novelty.42
Impact.55
Basis · grounding3 papers
[1]
paper
GL-29, an analogue of palustrin-2ISb, showed activity against C. albicans in MIC assays, demonstrating that palustrin-2 family members have antifungal activity.
doi: 10.3390/antibiotics11081048
[2]
paper
Amphipathic cationic AMPs interact with negatively charged microbial membranes; fungal ergosterol-rich membranes present a different electrostatic and lipid environment from bacterial membranes, relevant to selectivity.
doi: 10.1177/0022034516679973
[3]
paper
Selectivity of host defense peptides for pathogens over commensals and human cells is highlighted as a therapeutic advantage; antifungal applications are within the AMP therapeutic scope.
doi: 10.1038/s41573-019-0058-8
openupdated 2026-06-05

Can trimming the end of this peptide make it safer without making it weaker against bacteria?

One of the main obstacles to turning antimicrobial peptides into drugs is that they can rupture red blood cells. If removing the C-terminal ring reduces that toxicity while leaving the bacteria-killing activity intact, the result would be a shorter, cheaper peptide with a wider safety margin, making it a more realistic candidate for treating serious bacterial infections in people.

The hypothesis
The Rana box disulfide (C46-C50, within the C-terminal CKIGGGCPP motif) suppresses hemolysis without contributing to antimicrobial potency in palustrin-2CG1, such that a linear analogue truncated at residue ~48 retains full antibacterial MIC values against Gram-negative pathogens while showing reduced red blood cell lysis.
Why it’s plausible
The evidence from the GL-29 truncation study of the closely related palustrin-2ISb shows that removing the C-terminal seven residues (which include the Rana box) yields similar antimicrobial activity but lower hemolysis. Palustrin-2CG1 has the same C-terminal architecture (C46 and C50 with the canonical GGGCPP ring-closing motif). The anionic and cyclic Rana box may dampen electrostatic interaction with red blood cell membranes, whose outer leaflet phosphatidylcholine is zwitterionic, while the amphipathic core is sufficient for bacterial killing.
Why it matters
If confirmed, the therapeutic window of palustrin-2CG1 can be widened by removing the Rana box, yielding a shorter, less expensive linear analogue suitable for systemic use. This is directly actionable for SPPS optimization given the known cost constraints on 55-residue peptides.
Plausibility.50
Novelty.18
Impact.62
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC46 and C50 form the Rana box (CKIGGGCPP); positions identified by alignment to palustrin-2ISb literature.
[2]
paper
In palustrin-2ISb, the disulfide bridge and Rana box had negligible effect on antimicrobial activity; their removal reduced hemolysis and cytotoxicity.
doi: 10.3390/antibiotics11081048
[3]
paper
Outer monolayers of eukaryotic membranes are zwitterionic, limiting electrostatic-driven lysis; cancer and bacterial cells are more negative.
doi: 10.1177/0022034516679973
details expand to inspect
full evidence table1 metrics
metricvaluetool
ranking score 0.6093378067016602 boltz-2
3-letter notation
Gly-Thr-Ile-Ser-Ser-Leu-Cys-Glu-Gln-Glu-Arg-Asp-Ala-Asn-Glu-Asp-Glu-Val-Leu-Glu-Glu-Val-Lys-Arg-Gly-Ile-Trp-Asp-Ser-Ile-Lys-Thr-Phe-Gly-Lys-Lys-Phe-Ala-Leu-Asn-Ile-Met-Asp-Lys-Ile-Lys-Cys-Lys-Ile-Gly-Gly-Gly-Cys-Pro-Pro
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). Palustrin-2CG1 germ-killing peptide (pep-05657, v1). PeptideModel. https://peptidemodel.com/card/pep-05657
@peptide{pep05657,
  sequence = {GTISSLCEQERDANEDEVLEEVKRGIWDSIKTFGKKFALNIMDKIKCKIGGGCPP},
  target   = {antimicrobial},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 5 by signal overlap
references 3 papers
[2] supporting
[3] supporting
discussion no comments
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