pe
pep-10371 v1 CC-BY-SA-4.0

Gut-healing experimental peptide (CHEMBL3824179)

A lab-made peptide that switches on a gut-repair signal, studied for its potential to heal and strengthen the intestinal lining; experimental, not yet an approved drug.

statusbioassayed targetGLP-2R length30 aa refs1
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 5 / 5
prediction metrics openfold3-mlx 0.3.1
ipTM0.875
pTM0.680
avg pLDDT49.8
ranking score0.947
STRUCTURE · PEP-10371 × GLP-2R
ranking0.947
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
openfold3-mlx 0.3.1 · mmCIF ↓ download
sequence30 aa
151015202530
HGDGSFSDEMNTILD NLAARDFINWLIQTK
in the news 1 article
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 2026-06-05

Could chemically pinning this peptide into a helical shape make it stable enough for once-daily dosing?

Native GLP-2 breaks down within minutes in the bloodstream. A stabilised version could become a practical once-daily pill or injection for patients with intestinal failure, dramatically improving quality of life.

The hypothesis
Replacing the disordered NTIL segment (positions 11-14) with a rigidifying Aib-Pro staple or a lactam bridge between Asp20 and Lys30 would pre-organise the proposed binding helix (LAARDFINWLIQ, positions 17-28) and improve proteolytic resistance without disrupting the key hydrophobic contacts.
Why it’s plausible
Disordered peptide GLP receptor ligands are notoriously susceptible to DPP-IV and neutral endopeptidase cleavage. GLP-2 itself requires DPPIV protection at position 2 (the Ala2 to Gly substitution in this peptide already makes it a poorer DPP-IV substrate, but the peptide remains flexible). A Asp20-Lys30 lactam would span across the predicted helix, bracing it. Asp20 (position i) to Lys30 (position i+10) spans roughly 2.5 helical turns, a validated lactam bridge distance used in GLP-1R peptide stabilisation literature. The Trp25 indole ring would remain solvent-exposed and available for receptor contact.
Why it matters
Helix-stabilised GLP-2R agonists with DPP-IV resistance and reduced conformational entropy could have substantially extended in vivo half-lives compared to native GLP-2 (t1/2 ~7 min), making once-daily or even weekly dosing feasible.
Plausibility.60
Novelty.40
Impact.65
Basis · grounding3 computed/notes
[1]
sequenceAsp20 and Lys30 are separated by 10 residues, compatible with an i to i+10 lactam bridge spanning 2.5 alpha-helical turns
[2]
sequenceHis1-Gly2 N-terminus already disrupts DPP-IV cleavage motif (DPP-IV requires Ala or Pro at position 2); further stabilisation addresses other proteases
[3]
sequenceTrp25 is a known high-value receptor-contact residue in class B GPCR peptide ligands; bridging away from Trp preserves this contact
openupdated 2026-06-05

Does this peptide grip the GLP-2 receptor at a different spot than the body's own GLP-2 signal?

If true, it could produce a gut-healing effect with a safer side-effect profile than current GLP-2 drugs, which is relevant for patients recovering from intestinal surgery or living with short bowel syndrome.

The hypothesis
The peptide HGDGSFSDEMNTILDNLAARDFINWLIQTK binds GLP-2R with high-confidence interface geometry (ipTM 0.875), suggesting it engages the receptor's extracellular domain through a helical segment anchored by the C-terminal WLIQTK motif rather than mimicking the N-terminal histidine-dependent activation mode of native GLP-2.
Why it’s plausible
Native GLP-2 activates GLP-2R via an N-terminal His-Ala dipeptide that inserts into the transmembrane bundle. This peptide begins His-Gly-Asp instead, with Gly at position 2 likely preventing the canonical insertion. Yet the ipTM of 0.875 is strong, indicating a real predicted interface. The C-terminal WLIQTK is amphipathic and could stabilise an extracellular contact face distinct from the orthosteric agonist pocket, making this a potential partial agonist or biased ligand rather than a full GLP-2 mimetic.
Why it matters
If the peptide occupies an allosteric or non-canonical binding site on GLP-2R, it could modulate receptor signalling with a different efficacy or bias profile than native GLP-2, opening a route to gut-trophic agents that avoid the growth-promoting side-effects associated with full GLP-2R agonism.
Plausibility.55
Novelty.50
Impact.60
Basis · grounding3 computed/notes
[1]
structureopenfold3-mlx/complex ipTM=0.875, indicating high-confidence predicted interface with GLP-2R
[2]
sequencePosition 2 is Gly (not Ala as in GLP-2), likely disrupting canonical N-terminal insertion into the TMD bundle
[3]
sequenceC-terminal WLIQTK (positions 25-30) is amphipathic: Trp25, Ile27, Leu28 form a hydrophobic face; Gln29, Lys30 are polar/cationic
openupdated 2026-06-05

Could this peptide stimulate intestinal tissue growth without causing the fluid loss that full GLP-2 receptor activation can produce?

If true, patients with short bowel syndrome or chemotherapy-damaged intestines could benefit from a safer version of gut-repair therapy, one that builds tissue without causing problematic fluid shifts.

The hypothesis
GLP-2R activation by this peptide could promote intestinal crypt-cell protein synthesis through a GLP-2R/mTOR axis distinct from the cAMP/PKA pathway, based on the annotated GLP-2R target and prior evidence that GLP-2-stimulated protein synthesis in gut epithelial cells is mediated by a pathway separable from canonical GPCR second-messenger cascades.
Why it’s plausible
Published data on GLP-2-mediated signalling in HEK293 cells transfected with GLP-2R (DOI 10.1152/ajpendo.00620.2010) shows GLP-2 stimulates protein synthesis, with the paper suggesting this is amount-dependent and mechanistically separable. If this peptide binds GLP-2R but with altered coupling (due to its non-canonical N-terminus), it could selectively engage a beta-arrestin or PI3K-coupled arm rather than the cAMP arm, providing anabolic gut-trophic effects without the secretory-diarrhoea risk of full cAMP-driven agonism.
Why it matters
A biased GLP-2R agonist selective for the protein-synthesis arm over the cAMP-secretory arm would be valuable in clinical settings requiring gut mucosal repair, including inflammatory bowel disease, short bowel syndrome, and chemotherapy-induced mucositis.
Plausibility.45
Novelty.55
Impact.65
Basis · grounding1 paper · 2 computed/notes
[1]
paper
GLP-2 stimulates protein synthesis in HEK293/GLP-2R cells; mechanism appears partially separable from canonical GPCR signalling
doi: 10.1152/ajpendo.00620.2010
[2]
sequenceHis1-Gly2-Asp3 N-terminus differs from native GLP-2 His1-Ala2, likely altering TMD insertion and G-protein coupling efficiency
[3]
structureipTM=0.875 confirms predicted GLP-2R engagement, supporting the receptor as a real target
openupdated 2026-06-05

Does this peptide only take on a defined shape when it docks onto GLP-2R, rather than having a fixed structure in the bloodstream?

Peptides that fold on demand tend to bind their target more selectively, potentially reducing unwanted side-effects, which matters for any future drug built on this scaffold.

The hypothesis
The low pLDDT (49.8) of the predicted complex, despite a high ipTM (0.875), indicates that the peptide backbone is intrinsically disordered in isolation and undergoes coupled folding and binding upon GLP-2R engagement, with the FINWLIQ segment (positions 22-28) forming the primary ordered anchor.
Why it’s plausible
pLDDT below 50 across a 30-residue peptide signals little stable secondary structure in isolation, consistent with a disordered or flexible peptide. High ipTM alongside low pLDDT is the hallmark signature of a coupled-folding-upon-binding (induced fit) interaction seen in intrinsically disordered peptide ligands. The FINWLIQ stretch contains Phe22, Ile23, Asn24 (H-bond donor/acceptor), Trp25, Leu27, Ile28 (hydrophobic), which in an alpha-helical conformation would create a hydrophobic face capable of burying into a receptor groove. The preceding LAARD segment (positions 17-21) contains two Ala residues favouring helix nucleation.
Why it matters
Coupled folding-on-binding peptides often achieve high selectivity because entropic cost is paid only at the correct target interface; this property would make the peptide less likely to have off-target membrane activity and more amenable to half-life extension by helix-stabilising modifications.
Plausibility.70
Novelty.30
Impact.50
Basis · grounding3 computed/notes
[1]
structurepLDDT=49.8 indicates disorder in isolation; ipTM=0.875 indicates confident interface, consistent with induced-fit binding
[2]
sequenceLAARDFINWLIQ (positions 17-28): LAARD contains two Ala promoting helix; FINWLIQ provides a hydrophobic stripe on one helical face
[3]
sequenceN-terminal HGDGSFSDEM (positions 1-10) is rich in Ser, Gly, Asp, Glu, consistent with a disordered flexible tether
openupdated 2026-06-05

Is only the back half of this peptide doing the real work of binding to GLP-2R?

If a shorter version binds just as well, it would be cheaper to manufacture and more stable in the body, bringing a potential gut-healing drug closer to clinical use.

The hypothesis
Truncating the disordered N-terminal segment HGDGSFSDEM (positions 1-10) would preserve or enhance GLP-2R binding affinity, because this segment contributes disorder and negative charge that counteracts receptor engagement, while the structured C-terminal core NTILDNLAARDFINWLIQTK (positions 11-30) carries the binding pharmacophore.
Why it’s plausible
The pLDDT of 49.8 averaged across the full 30-mer likely reflects substantial disorder in the N-terminal HGDGSFSDEM decapeptide (rich in Gly, Ser, Asp, Glu, all disorder-promoting). The C-terminal 20-mer NTILDNLAARDFINWLIQTK contains Ile13, Leu15, Ala18, Arg19, Asp20, Phe22, Ile23, Trp25, Leu27, Ile28, providing hydrophobic bulk and a cationic Arg for salt-bridge formation. If the N-terminal segment is a disordered entropic penalty with no receptor contacts, removing it would improve the on-rate and potentially the Kd.
Why it matters
Identifying a minimal binding fragment would reduce peptide length, lower synthesis cost, improve metabolic stability, and facilitate further optimisation toward a clinical candidate.
Plausibility.55
Novelty.35
Impact.55
Basis · grounding3 computed/notes
[1]
sequencePositions 1-10 (HGDGSFSDEM): Gly2, Gly5, Ser6, Ser8 are helix-breaking; Asp3, Asp8, Glu10 add negative charge; no hydrophobic core
[2]
sequencePositions 11-30 (NTILDNLAARDFINWLIQTK): contains Ile, Leu, Ala, Phe, Trp, Ile hydrophobic cluster and Arg19, Lys30 for ionic contacts
[3]
structurepLDDT=49.8 indicates disorder, likely contributed disproportionately by the N-terminal segment
details expand to inspect
full evidence table1 metrics
metricvaluetool
EC50 0.22 nM GPCRDB/ChEMBL
structural qualityopenfold3
0
metricvaluenote
gpde0.746global PDE — lower = better
disorder0.223fraction disordered
chain pair ipTM (A, B)0.875interface quality
3-letter notation
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys
recipeopenfold3-mlx 0.3.1
parametervalue
modelopenfold3-mlx 0.3.1
weightsaedd8f3eb814e392…
hardwareapple_m4_base_16gb
mlx version0.31.1
python3.14.3
random seed42
msa strategycolabfold
diffusion samples1
runtime647s
predicted bymlx@peptide
predicted at2026-04-22
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1
citationbibtex
peptidemodel (2026). Gut-healing experimental peptide (CHEMBL3824179) (pep-10371, v1). PeptideModel. https://peptidemodel.com/card/pep-10371
@peptide{pep10371,
  sequence = {HGDGSFSDEMNTILDNLAARDFINWLIQTK},
  target   = {glp-2r},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
clinical trials 0 trials · checked 2026-05-22
0
no registered clinical trials as of 2026-05-22; we'll re-check periodically
references 1 papers
[1] supporting
discussion no comments
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