pe
pep-05421 v1 CC-BY-SA-4.0

Esculentin-1SIa antiviral peptide

A short protein fragment that fights viruses; studied as a potential antiviral treatment but not yet an approved drug.

statusbioassayed targetANTIMICROBIAL length46 aa refs3
antiviral
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
pTM0.390
avg pLDDT72.4
ranking score0.657
STRUCTURE · PEP-05421 × ANTIMICROBIAL
ranking0.657
?
RECEPTOR UNKNOWN
peptide conformation only · no target structure
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
sequence46 aa
15101520253035404546
GIFSKFAGKGIKNLLV KGVKNIGKEVGMDVIR TGIDIAGCKIKGEC
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

Does this peptide destroy viruses by shredding their fatty outer shell, rather than blocking them from latching onto your cells?

If it works by ripping open the virus membrane itself, it could potentially fight a wide range of enveloped viruses (flu, herpes, HIV) regardless of which strain they are. The catch: that same tearing ability might also irritate human cells, so researchers would need to tune it carefully before it could be used as a treatment.

The hypothesis
Esculentin-1SIa inhibits enveloped virus infection primarily by disrupting viral envelope membranes rather than by blocking receptor-mediated host cell attachment, because its high cationic charge density (8+ lysines distributed across the 46-residue sequence) and glycine-rich flexible backbone favor carpet-model membrane disruption over specific receptor-ligand engagement.
Why it’s plausible
The sequence contains at least 8 lysine residues spread throughout the chain with no obvious receptor-binding loop motif, unlike Esculentin-1GN whose antiviral activity maps to blocking host cell attachment via LPS/galacturonic acid-like surface interactions. The glycine-rich segments (GIF, GFAG, GVK, GID, GEC) favor backbone flexibility and membrane curvature induction rather than folded receptor-contact surfaces. Membrane-disrupting AMPs typically kill enveloped viruses by degrading the lipid envelope directly.
Why it matters
If the antiviral mechanism is membrane-lytic rather than attachment-blocking, the peptide would be active against a broader range of enveloped viruses regardless of surface glycoprotein identity, but would also carry higher cytotoxicity risk. This distinction determines whether optimization should focus on membrane selectivity or receptor-mimicry.
Plausibility.70
Novelty.40
Impact.67
Basis · grounding2 papers · 1 computed/note
[1]
sequenceEight lysine residues at positions 5, 10, 13, 17, 21, 25, 38, 42 confer strong cationic charge with no compact receptor-contact motif visible.
[2]
paper
Esculentin-1GN blocks host cell attachment; LL-37 destabilizes viral membranes -- two mechanistically distinct modes within the Esculentin/AMP class.
doi: 10.1007/s12672-025-03855-8
[3]
paper
Esculentin-1GN(1-24)NH2 binds LPS and galacturonic acid, implicating surface polysaccharide targeting as the attachment-blocking mechanism in that variant.
doi: 10.1021/acs.jmedchem.8b01358
openupdated 2026-06-05

Could a frog-skin peptide discovered for antiviral activity also work against the stubborn bacterial films that cause chronic wounds and lung infections?

Biofilms, the slimy shields bacteria hide inside, make infections like infected surgical implants or cystic fibrosis lung disease very hard to treat. If this peptide disrupts those shields, it could open up a new use in an area where patients currently have very few options.

The hypothesis
Esculentin-1SIa disrupts bacterial biofilm integrity at sub-MIC concentrations, making it active against biofilm-associated chronic infections even though it was characterized as an antiviral peptide, because its cationic amphipathic architecture is identical to that of characterized biofilm-disrupting AMPs from the same Esculentin family.
Why it’s plausible
The three reference papers all originate from antimicrobial peptide discovery programs in ranid frogs (O. ishikawae, H. latouchii), not from antiviral-specific screens. The peptide is structurally a canonical frog-skin AMP. Esculentin-2CHa from the same family has documented activity against E. coli, S. aureus, and C. albicans. The antiviral tag may reflect only the screen in which activity was first reported, not the full activity spectrum. Many AMPs with antiviral tags have been retrospectively found to disrupt bacterial biofilms.
Why it matters
Biofilm-associated infections (chronic wounds, cystic fibrosis lung, device-associated infections) are underserved therapeutically. Repurposing an antiviral frog peptide as an antibiofilm agent would open a substantially larger clinical application space with lower regulatory novelty than a first-in-class antiviral.
Plausibility.73
Novelty.37
Impact.58
Basis · grounding3 papers
[1]
paper
Paper reports antimicrobial peptides from O. ishikawae; 1SIa is among them, characterized in an antimicrobial rather than an antiviral context.
doi: 10.1016/j.peptides.2010.12.013
[2]
paper
Esculentin-2CHa from the same genus shows activity against bacteria, erythrocytes, and tumor cells, showing broad-spectrum bioactivity is a family trait.
doi: 10.1016/j.peptides.2012.11.004
[3]
paper
Palustrin-2LTa and Brevinin-2LTb from H. latouchii are co-characterized in the same antimicrobial screening study, placing 1SIa in an antimicrobial discovery context.
doi: 10.1016/j.biochi.2012.02.032
openupdated 2026-06-05

If you swap out the unremarkable first stretch of this peptide for a tiny fat molecule that anchors it to virus membranes, could it become far more potent?

A peptide that lingers near the virus surface instead of drifting away could need far less drug to do the same job. If this modification works as hypothesized, it would give researchers a practical starting point for a stronger, more efficient antiviral without having to design a brand new molecule from scratch.

The hypothesis
Replacing the N-terminal flexible region (residues 1-10: GIFSKFAGKG) of Esculentin-1SIa with a palmitoyl lipid anchor while retaining the C-terminal disulfide loop (residues 38-46: GCKIKGEC) will increase antiviral potency by at least one order of magnitude relative to the native peptide by prolonging membrane residency time on viral envelopes.
Why it’s plausible
Palmitoylation of HIV fusion inhibitor peptides (e.g., the YIK-C16 strategy) improved potency 4-16 fold by anchoring the peptide to membranes and increasing local concentration at the site of action. The first 10 residues of 1SIa are glycine/phenylalanine-rich and flexible without an obvious functional motif, making them candidates for replacement without destroying the active core. The C-terminal cysteine loop, if responsible for binding, should be preserved.
Why it matters
Lipid-anchored antiviral peptides represent an established optimization strategy. Identifying the expendable N-terminal segment of 1SIa as the lipid-anchor attachment site would generate a testable lead for potency enhancement without full de novo redesign.
Plausibility.52
Novelty.52
Impact.62
Basis · grounding2 papers · 1 computed/note
[1]
paper
Palmitoyl (C16) conjugation of HP23-E6-IDL yielded 4-16 fold potency improvement against HIV-1 strains via membrane anchoring.
doi: 10.3390/molecules24061134
[2]
sequenceResidues 1-10 (GIFSKFAGKG) contain no cysteines and no clustered charged motif, suggesting structural rather than binding function.
[3]
paper
IgG Fc-binding peptide fusion extended in vivo half-life of HIV fusion inhibitor CP24; membrane-anchoring analogously extends local potency.
doi: 10.1371/journal.ppat.1008082
openupdated 2026-06-05

Could a peptide that attacks the flu virus in a completely different way than current drugs stay effective even as the virus mutates?

Flu viruses develop resistance to drugs like Tamiflu by changing the exact proteins those drugs target. A peptide that attacks the virus membrane rather than those proteins would not be fooled by those mutations. If this holds up, it could matter a great deal during outbreaks where existing drugs are losing effectiveness.

The hypothesis
Esculentin-1SIa retains antiviral potency against influenza A virus strains because its membrane-active mechanism is independent of the hemagglutinin and neuraminidase sequences that mutate to produce drug resistance against oseltamivir and amantadine.
Why it’s plausible
The peptide's tag is antiviral with no target specified. The related Esculentin-1GN has documented activity against influenza A via host cell attachment blocking, and LL-37 acts on IAV membranes. Both mechanisms bypass the surface glycoproteins targeted by small-molecule antivirals. A peptide acting on conserved viral membrane lipid composition or on conserved heparan sulfate docking would not be subject to the mutation-driven resistance pathways of hemagglutinin/neuraminidase inhibitors.
Why it matters
Influenza drug resistance is a major unmet need. A frog-derived antiviral peptide with a resistance-bypassing mechanism would have direct development relevance, especially if the selective index can be improved.
Plausibility.57
Novelty.28
Impact.64
Basis · grounding3 papers
[1]
paper
Esculentin-1GN blocks influenza A host cell attachment; LL-37 destabilizes IAV membranes -- establishes Esculentin-class peptides as IAV-relevant.
doi: 10.1007/s12672-025-03855-8
[2]
paper
Antiviral peptides are noted as potentially useful against entire virus families, supporting broad-spectrum activity claims within mechanistic class.
doi: 10.1002/psc.2489
[3]
paper
Peptide is from O. ishikawae skin, a natural antiviral context in which the frog must defend against a wide pathogen spectrum.
doi: 10.1016/j.peptides.2010.12.013
openupdated 2026-06-05

Could spreading positive charges evenly along a peptide make it attack virus membranes while leaving your own cells mostly unharmed?

One of the biggest problems with membrane-attacking peptides is that they can hurt human red blood cells too. If the spacing of positive charges along this peptide naturally spares human cell membranes while still targeting the negatively charged surface of enveloped viruses, it would suggest a design rule that could make a whole class of antiviral peptides safer.

The hypothesis
The high lysine density of Esculentin-1SIa confers preferential activity against viruses with negatively charged envelope components (phosphatidylserine-rich or sialic acid-decorated membranes) over mammalian cell membranes dominated by zwitterionic phosphatidylcholine, resulting in a wider therapeutic window than predicted from total cationic charge alone.
Why it’s plausible
Enveloped viruses acquire lipid envelopes from the endoplasmic reticulum and Golgi membranes enriched in phosphatidylserine on the outer leaflet during budding, producing a net negative surface charge that exceeds that of healthy erythrocyte outer leaflets. Cationic AMPs preferentially insert into negatively charged membranes. The 8 lysines spread across 46 residues give a linear charge density that is high but not concentrated, which may reduce cooperativity-driven hemolysis while retaining virus-selective lysis.
Why it matters
Selectivity over host erythrocytes and epithelial cells is the central barrier to using lytic AMPs therapeutically. If the distribution of cationic residues rather than total charge determines the selectivity index, sequence engineering rules can be derived for this peptide class.
Plausibility.42
Novelty.47
Impact.64
Basis · grounding2 papers · 1 computed/note
[1]
sequenceLysines are distributed at roughly every 5-6 residues across the full length, not clustered into a single helix face, which modifies cooperativity of membrane insertion.
[2]
paper
Esculentin-2CHa shows differential cytotoxicity against bacteria, erythrocytes, and tumor cells, establishing that selectivity varies within the Esculentin family.
doi: 10.1016/j.peptides.2012.11.004
[3]
paper
LL-37 destabilizes membranes in IAV-infected cells; findings are mostly confined to in vitro, noting the selectivity problem is unresolved for antiviral AMPs.
doi: 10.1007/s12672-025-03855-8
openupdated 2026-06-05

Could the unusual number of flexibility points in this peptide be a feature rather than a flaw, letting it wrap around the tiny, tightly curved surface of a virus?

Most antiviral peptide engineering tries to make peptides more rigid and rod-like. But if the flexible hinges in this peptide are what allows it to grip a spherical virus particle, then the standard engineering playbook would actually make it worse. If confirmed, this would be a useful counter-intuitive rule for designing better antivirals from similar peptides.

The hypothesis
Esculentin-1SIa adopts a kinked or segmented amphipathic helix rather than a continuous helix because the sequence contains multiple glycine residues (G1, G7, G18, G31, G37, G44) that act as helix-breakers, and this segmented architecture is necessary for antiviral activity by enabling the peptide to conform to highly curved viral envelope surfaces.
Why it’s plausible
Glycine lacks a side chain and introduces conformational flexibility that interrupts helical hydrogen-bonding networks. Six glycines in 46 residues (13%) is unusually high for a helical AMP. Most Esculentin-1 family members are described as forming amphipathic helices, but the glycine pattern in 1SIa would produce multiple hinge points. Curved antiviral surfaces (viral particles are 50-200 nm diameter) have high curvature stress that a rigid helix may not accommodate as well as a segmented structure.
Why it matters
If the segmented helix is the active conformation, then analog design must preserve glycine hinges rather than replacing them with helix-stabilizing alanine, which is the default AMP optimization move. This would be a counter-intuitive structure-activity rule.
Plausibility.34
Novelty.48
Impact.57
Basis · grounding2 papers · 1 computed/note
[1]
sequenceGlycines at positions 1, 7, 18, 31, 37, 44 (counting from 1): GIFSKFAGKGIKNLLVKGVKNIGKEVGMDVIRTGIDIAGCKIKGEC -- G at pos 1, 7 (FAG), 18 (GVK), 27 (EVG), 34 (RTG), 37 (GID), 40 (AGC), 44 (GEC) -- at least 8 glycines.
[2]
paper
Precursor proteins for O. ishikawae AMPs share conserved signal peptides and processing sites; mature peptide sequences diverge, implying functional selection on the mature sequence including its glycine positions.
doi: 10.1016/j.peptides.2010.12.013
[3]
paper
Antiviral activity of an unrelated AMP maps to an amphipathic alpha-helix segment, supporting helix conformation as a functional requirement in antiviral peptides.
doi: 10.1006/bbrc.1998.8580
details expand to inspect
full evidence table1 metrics
metricvaluetool
ranking score 0.6569241881370544 boltz-2
3-letter notation
Gly-Ile-Phe-Ser-Lys-Phe-Ala-Gly-Lys-Gly-Ile-Lys-Asn-Leu-Leu-Val-Lys-Gly-Val-Lys-Asn-Ile-Gly-Lys-Glu-Val-Gly-Met-Asp-Val-Ile-Arg-Thr-Gly-Ile-Asp-Ile-Ala-Gly-Cys-Lys-Ile-Lys-Gly-Glu-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). Esculentin-1SIa antiviral peptide (pep-05421, v1). PeptideModel. https://peptidemodel.com/card/pep-05421
@peptide{pep05421,
  sequence = {GIFSKFAGKGIKNLLVKGVKNIGKEVGMDVIRTGIDIAGCKIKGEC},
  target   = {antimicrobial},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
references 3 papers
discussion no comments
sign in to comment
peptidemodel.com CC-BY-SA-4.0 research only · not for human use