pe
pep-10339 v1 CC-BY-SA-4.0

Lab peptide that binds a brain signaling receptor (CHEMBL604373)

An experimental peptide made in a lab that latches onto a brain receptor linked to pain, mood, and appetite; used only as a research tool, not a medicine.

statusbioassayed targetGALR1 length21 aa refs6
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 boltz-2 1.0
ipTM0.872
pTM0.860
avg pLDDT78.6
ranking score0.803
STRUCTURE · PEP-10339 × GALR1
ranking0.803
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence21 aa
1510152021
GWTLNSA GYLLGPP KPQQFLL
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

Could we stop seizures by flipping just one molecular switch, instead of two at once?

If this holds, it would tell researchers exactly which receptor to target when developing new epilepsy drugs, potentially leading to treatments with fewer side effects. People with seizure disorders who do not respond to current medications could benefit from more precisely designed therapies.

The hypothesis
Pep-10339, by engaging GALR1 selectively without activating GALR2, suppresses hippocampal seizure activity through Gi-mediated reduction of adenylyl cyclase rather than through the Gq/PLC pathway activated by GALR2, making its anticonvulsant mechanism mechanistically distinct from that of the pan-agonist galnon.
Why it’s plausible
GALR1 couples to Gi/Go, while GALR2 couples to Gq/11. Anticonvulsant effects of galanin system activation are well documented (galnon, galmic studies in the references), but which receptor subtype and which downstream cascade is primarily responsible remains unclear. If pep-10339 is GALR1-selective (as hypothesized from its truncated C-terminus), its anticonvulsant activity would proceed exclusively through Gi-dependent hyperpolarization and cAMP suppression, not through the PLC/IP3/PKC cascade. This distinction matters because GALR2-Gq signaling has neurotrophic and pro-excitatory components that could limit net anticonvulsant efficacy.
Why it matters
Mechanistic disambiguation between GALR1-Gi and GALR2-Gq in anticonvulsant responses would clarify which receptor subtype to target for epilepsy drug development, a key unresolved question in the galanin receptor field.
Plausibility.53
Novelty.38
Impact.63
Basis · grounding3 papers
[1]
paper
Reviews GALR1 (Gi) vs GALR2 (Gq) coupling and discusses anticonvulsant role of galanin receptor system
doi: 10.1517/14728222.2015.1072513
[2]
paper
Galmic at intrahippocampal administration inhibits status epilepticus; galnon and galmic are pan-agonists with multiple off-target interactions
doi: 10.3389/fendo.2012.00146
[3]
paper
Human GalR2 cloning and expression characterization including signaling pathway analysis
doi: 10.1006/bbrc.1998.8133
openupdated 2026-06-05

Could the same compound that calms seizure activity also reduce overeating?

If this repurposing idea pans out, researchers might be able to develop a single compound that addresses both neurological and metabolic conditions. For people struggling with obesity or compulsive overeating, this could open a new treatment direction that works through the brain's natural appetite circuits.

The hypothesis
The GALR3-expressing hypothalamus and pituitary could be a secondary site of action for pep-10339 relevant to feeding regulation, because GALR3 mRNA is highest in these tissues and the N-terminal galanin pharmacophore present in pep-10339 activates GALR3 at micromolar concentrations sufficient to modulate hypothalamic feeding circuits.
Why it’s plausible
GALR3 mRNA is most abundant in rat hypothalamus and pituitary (10.1074/jbc.273.36.23321). The N-terminal galanin pharmacophore (GWTLNSAGYLLG) activates all three receptor subtypes, and pep-10339 retains this pharmacophore intact. While pep-10339 is annotated as a GALR1 tool compound, when delivered centrally or in a hypothalamic context, it would be expected to engage GALR3 in these feeding-relevant nuclei. Galanin system activation modulates food intake through hypothalamic circuits, and GALR3 involvement in this has been studied but not pharmacologically resolved with selective ligands.
Why it matters
Identifying a dual GALR1/GALR3 activity in hypothalamic feeding circuits would open a repurposing path toward metabolic disorders such as obesity or hyperphagia, extending the peptide's utility beyond CNS pain and mood applications.
Plausibility.52
Novelty.48
Impact.53
Basis · grounding2 papers · 1 computed/note
[1]
paper
GALR3 mRNA highest in rat hypothalamus and pituitary; also detected in spinal cord and cortex but absent from hippocampus
doi: 10.1074/jbc.273.36.23321
[2]
paper
Galanin system modulates feeding; galnon evaluated in feeding models
doi: 10.3389/fendo.2012.00146
[3]
sequenceN-terminal GWTLNSAGYLLG is the universal galanin receptor activation pharmacophore, present intact in pep-10339
openupdated 2026-06-05

What if bending a straight-chain peptide into a loop made it survive long enough to be useful as a medicine?

Most peptides break down in the body within minutes, which makes them hard to study or use as drugs. If this engineering approach works, it could produce a more stable version of the compound that lasts long enough for proper animal studies, moving the science closer to a real therapeutic.

The hypothesis
Cyclization of pep-10339 via a lactam bridge between the lysine at position 15 (K15) and the C-terminal leucine carboxylate would lock the GPPKPQQFLL C-terminal segment into a defined conformation that improves both proteolytic stability and GALR1 binding selectivity over GALR2.
Why it’s plausible
The sequence contains K15 flanked by two prolines (P14 and P16), a configuration that is geometrically favorable for forming an intramolecular lactam between the K15 epsilon-amine and the C-terminal carboxylate. Linear peptides with exposed proline-lysine segments are known substrates for proline-specific endopeptidases. Cyclization via this lysine would sterically protect the backbone from endoproteolysis, a key liability for CNS-targeted peptides. The axis-hit data (half-life references) highlight that unmodified linear peptides typically have t1/2 of 2-30 minutes. Constraining the C-terminal loop via K15 bridging would also fix the orientation of the FLL hydrophobic tail relative to GALR1's binding vestibule.
Why it matters
A cyclized pep-10339 analog with improved half-life and maintained GALR1 selectivity would be a significantly more useful research tool for in vivo galanin receptor pharmacology studies, addressing the primary metabolic liability of linear galanin-derived peptides.
Plausibility.48
Novelty.50
Impact.53
Basis · grounding3 computed/notes
[1]
sequenceK15 flanked by P14 and P16 in GWTLNSAGYLLGPPKPQQFLL; geometry favorable for head-to-sidechain cyclization
[2]
sourceUnmodified linear peptides typically exhibit serum half-life of 2-30 minutes, motivating cyclization strategies
[3]
sourceAxis hit: D-amino acid and structural modifications improve proteolytic stability; design rationale for constrained peptides
openupdated 2026-06-05

Could we calm anxiety through the brain's galanin system without touching dopamine, the way older compounds do?

Existing non-peptide compounds that reduce anxiety in animals also accidentally hit dopamine and other receptors, which creates noise in research and potential side effects in patients. If this peptide works cleanly, it could become both a sharper scientific tool and, eventually, a foundation for anxiety treatments that do not carry the baggage of current approaches.

The hypothesis
Pep-10339 reduces anxiety-like behavior in rodent models by activating GALR1 in the amygdala and locus coeruleus, and this anxiolytic effect is independent of the off-target dopaminergic and melanocortinergic interactions that limit galnon.
Why it’s plausible
Galnon produces anxiolytic effects in forced swim and elevated plus maze models, but its utility is compromised by interactions with D2 dopamine, ghrelin, and melanocortin receptors (10.3389/fendo.2012.00146). Pep-10339, as a peptidic GALR1 agonist, is structurally dissimilar to monoamine ligands and would not be expected to bind D2 receptors. GALR1 is expressed in the amygdala and locus coeruleus, regions central to anxiogenic circuit modulation. A peptidic agonist that achieves anxiolysis without these off-targets would represent a cleaner pharmacological tool and potentially a superior therapeutic scaffold.
Why it matters
Demonstrating clean anxiolytic activity without dopaminergic off-target effects would validate GALR1-selective peptidic agonism as a tractable anxiety pharmacology approach, addressing a major gap left by non-peptide pan-agonists.
Plausibility.55
Novelty.35
Impact.55
Basis · grounding3 papers
[1]
paper
Galnon anxiolytic-like activity in forced swim test; binding data against GALR1 expressing membranes
doi: 10.1016/j.npep.2007.05.001
[2]
paper
Galnon and galmic off-target interactions with D2 dopamine, ghrelin, and melanocortin receptors explicitly noted as limiting factors
doi: 10.3389/fendo.2012.00146
[3]
paper
Galanin receptors as targets for neurological disease including anxiety disorders
doi: 10.1517/14728222.2015.1072513
openupdated 2026-06-05

Could swapping out just one building block of this peptide destroy its ability to work?

If a single amino acid turns out to drive most of the binding, chemists would know exactly what to preserve when redesigning the molecule to be more stable or pill-friendly. This kind of knowledge could accelerate the development of smaller, more drug-like compounds based on this peptide.

The hypothesis
The tryptophan at position 2 (W2) of pep-10339 is a critical contact residue for GALR1 binding, such that substitution with alanine reduces affinity to the same extent as deletion of the entire C-terminal half of the peptide.
Why it’s plausible
Position 2 tryptophan (W2) is one of the most conserved residues across galanin orthologs and is present in essentially all species' galanin sequences. Tryptophan side chains frequently form cation-pi and aromatic stacking contacts in GPCR binding pockets. The Boltz-2 prediction with ipTM 0.872 suggests a compact, well-defined binding interface in which the N-terminal GW motif is likely buried in the receptor's orthosteric site. Literature on galanin structure-function consistently identifies W2 as a hot-spot residue, and W2A or W2F substitutions have been explored as chemical tools.
Why it matters
Confirming W2 as a primary binding hot-spot would establish the minimal N-terminal anchor for GALR1 engagement and guide design of peptidomimetic or stapled analogs that preserve this contact while improving metabolic stability.
Plausibility.80
Novelty.13
Impact.42
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceW at position 2 of GWTLNSAGYLLGPPKPQQFLL; tryptophan is the most conserved residue across galanin orthologs
[2]
structureBoltz-2 ipTM 0.872 indicates high-confidence complex; N-terminal residues are the activation pharmacophore and W2 is expected to be a key contact
[3]
paper
Structure-function study on galanin identifying different pharmacophores within the sequence for the three receptor subtypes
doi: 10.1074/jbc.272.51.31949
openupdated 2026-06-05

Does a stiff bend midway through this peptide act like an aiming mechanism for the business end of the molecule?

If disrupting this hinge kills binding, it confirms that the shape of the molecule matters as much as its chemical composition. Drug designers could then build constrained analogs, essentially small molecules or stapled peptides that mimic this shape, which would be more potent and survive longer in the body.

The hypothesis
The proline-proline motif at positions 13-14 of pep-10339 (GPPK) acts as a rigid turn that positions the C-terminal hydrophobic cluster FLL into the extracellular binding vestibule of GALR1, and disrupting this turn by substituting either proline will reduce binding affinity by at least 10-fold.
Why it’s plausible
The PP dinucleotide in a GPPKP context imposes a strong backbone constraint that is conserved in native galanin. The high ipTM of 0.872 from Boltz-2 suggests a well-defined complex, and the FLL hydrophobic tail is structurally positioned to engage a hydrophobic pocket in GALR1. Disrupting the proline turn geometry would misposition this tail relative to the receptor binding vestibule.
Why it matters
Identifying the PP turn as a critical structural hinge would inform minimal pharmacophore design and could guide creation of constrained analogs with improved potency and metabolic stability.
Plausibility.42
Novelty.48
Impact.52
Basis · grounding1 paper · 2 computed/notes
[1]
structureBoltz-2 ipTM 0.872 indicates a high-confidence complex, consistent with a specific and structured binding mode
[2]
sequencePositions 13-14 are PP (GWTLNSAGYLLGPPKPQQFLL); this PP motif is a backbone constraint element present in native galanin
[3]
paper
Structure-function work on galanin receptor subtypes identifies specific pharmacophores within galanin sequence
doi: 10.1074/jbc.272.51.31949
details expand to inspect
full evidence table1 metrics
metricvaluetool
Ki 0.08 nM GPCRDB/ChEMBL
structural qualityopenfold3
metricvaluenote
gpde0.795global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Gly-Trp-Thr-Leu-Asn-Ser-Ala-Gly-Tyr-Leu-Leu-Gly-Pro-Pro-Lys-Pro-Gln-Gln-Phe-Leu-Leu
recipeboltz-2 1.0
parametervalue
modelboltz-2 1.0
weights
hardwarenvidia_nim_api
mlx version
python
random seed
msa strategynone
diffusion samples1
runtime
predicted bymlx@peptide
predicted at2026-04-24
citationbibtex
peptidemodel (2026). Lab peptide that binds a brain signaling receptor (CHEMBL604373) (pep-10339, v1). PeptideModel. https://peptidemodel.com/card/pep-10339
@peptide{pep10339,
  sequence = {GWTLNSAGYLLGPPKPQQFLL},
  target   = {galr1},
  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 6 papers
[1]
Galanin receptors as a potential target for neurological disease
Freimann, K. et al. Expert Opinion on Therapeutic Targets 2015
supporting
[2]
Cloned Human and Rat Galanin GALR3 Receptors
Smith, K. et al. Journal of Biological Chemistry 1998
supporting
[3]
Galanin Receptors and Ligands
Webling, K. et al. Frontiers in Endocrinology 2012
supporting
[5] supporting
[6]
Cloning and Expression of the Human Galanin Receptor GalR2
Bloomquist, B. et al. Biochemical and Biophysical Research Communications 1998
supporting
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