TIP39: brain peptide that switches on the PTH1 receptor
A natural brain-signaling peptide that strongly activates the parathyroid hormone 1 receptor (PTH1R), a target involved in bone and calcium signaling; used only as a lab research tool.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
Snapshot
Class: Endogenous neuropeptide; PTH2 receptor agonist
Evidence tier: In vitro / assay evidence
Status: No approved therapeutic status identified
Best-supported effect: Potent and selective activation of the PTH2 receptor in cell-based assays — EC50 ≈ 0.5 nM at human PTH2R and ≈ 0.8 nM at rat PTH2R; substantially more potent than parathyroid hormone at the rat receptor in the same assay system
Main caveat: Evidence is limited to in vitro receptor activation assays from a single 1999 publication; no animal efficacy data or human data are present
What this is
TIP-39 (Tuberoinfundibular Peptide of 39 residues) is an endogenous 39-amino acid peptide originally isolated from bovine hypothalamus. It was identified as a potent and selective agonist at the parathyroid hormone 2 receptor (PTH2R), a G protein-coupled receptor expressed in pituitary regions relevant to hormone secretion and in spinal cord areas associated with pain processing. In cell-based assays using synthetic TIP-39, the peptide was substantially more potent than parathyroid hormone (PTH) at the rat PTH2R. Proposed biological roles in hormone secretion and pain signaling are mechanistic hypotheses based on receptor expression patterns; functional in vivo roles are not characterized.
Evidence map
| Evidence layer | Grade | What it supports |
|---|---|---|
| Human | None identified | No human trial, observational, or case-report data are identifieds available literature |
| Animal | None identified | No animal efficacy data are individually extracted from the available literature |
| In vitro | Weak | PTH2R agonist activity confirmed in human and rat receptor-activation assays; sub-nanomolar EC50 values reported in a single peer-reviewed publication (Usdin et al., 1999); no independent replication data present in available literature |
| Computational | None identified | No structure prediction or docking data are attached |
| Mechanism | Plausible | PTH2R agonism supported by functional in vitro assay data; downstream pathway characterization and in vivo mechanism are not individually extracted from the available literature |
Claim check
| Claim | Verdict | Evidence layer | Confidence |
|---|---|---|---|
| Activates the human PTH2 receptor in vitro | Supported (in vitro) | In vitro assay | High — single primary paper; assay format details not fully described in source |
| More potent than PTH at the rat PTH2 receptor in cell-based assays | Supported (in vitro) | In vitro assay | High — same single-study limitation applies |
| Modulates pituitary hormone secretion or spinal pain signaling in vivo | Not established | In vitro (receptor expression context only) | Low |
| Therapeutic utility in any clinical indication | Not established | None | Low |
Assay conditions
This section reports concentrations used in in vitro assays. It does not establish animal or human exposure.
| Context | System | Assay condition | Timepoint | Endpoint | Limitation |
|---|---|---|---|---|---|
| Receptor activation assay | Human PTH2 receptor (expressed system) | Synthetic TIP-39; concentration series | Not individually extracted | EC50 ≈ 0.5 ± 0.12 nM | Single publication; assay format and cell-line details not described in available literature; no in vivo or human translation established |
| Receptor activation assay | Rat PTH2 receptor (expressed system) | Synthetic TIP-39; concentration series | Not individually extracted | EC50 ≈ 0.8 ± 0.3 nM | Single publication; same limitations apply |
| Comparative assay (reference) | Rat PTH2 receptor (expressed system) | Parathyroid hormone (PTH); concentration series | Not individually extracted | EC50 ≈ 49 ± 23 nM (PTH reference) | Comparator datum only; no in vivo comparison established |
Assay limitations
- All quantitative evidence derives from receptor-activation assays in one publication. No independent replication data are present.
- Assay system details — including cell line, receptor expression system, and assay readout (e.g., cAMP, HTRF, or other) — are not individually described in the available literature.
- In vitro EC50 values characterize receptor agonism in an artificial system; they do not establish in vivo potency, bioavailability, pharmacokinetics, CNS penetration, or therapeutic efficacy.
- Proposed roles in pituitary hormone secretion and spinal pain signaling derive from receptor distribution context, not from functional or behavioral endpoint data.
- No animal toxicology, pharmacokinetic, or safety data are present in the available literature.
- No human data of any kind are present in the available literature.
Mechanism
TIP-39 acts as an agonist at the parathyroid hormone 2 receptor (PTH2R), a class B G protein-coupled receptor. In functional cell-based assays, synthetic TIP-39 activated both human and rat PTH2R at sub-nanomolar concentrations — approximately 60-fold more potent than PTH at the rat receptor in the same system. PTH2R is expressed in pituitary regions associated with hormone secretion and in spinal cord areas linked to pain processing, which forms the basis for proposals that TIP-39 may participate in neuroendocrine and pain-related signaling. These proposed roles are mechanistic hypotheses extrapolated from receptor expression and in vitro activity; no in vivo characterization of downstream effects is present.
Chemistry
| Field | Value |
|---|---|
| Amino-acid sequence (one-letter) | SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP |
| Amino-acid chain (three-letter) | H-Ser-Leu-Ala-Leu-Ala-Asp-Asp-Ala-Ala-Phe-Arg-Glu-Arg-Ala-Arg-Leu-Leu-Ala-Ala-Leu-Glu-Arg-Arg-His-Trp-Leu-Asn-Ser-Tyr-Met-His-Lys-Leu-Leu-Val-Leu-Asp-Ala-Pro |
| Length | 39 amino acids |
| Topology | Linear |
| N-terminus | Free amine (H–) |
| C-terminus | Free acid (–OH) |
| Modifications | None reported in available literature |
| Origin | Originally isolated from bovine hypothalamus; assay data used synthetic form |
| Molecular weight | Not provided in available literature |
| Formula | Not provided in available literature |
| CAS | Not provided in available literature |
| Sequence confidence | Needs review — sequence derives from a single vendor catalog entry citing Usdin et al. (1999); cross-verification against primary sequence databases not performed in this card's authoring pass |
Open questions
- Animal translation: No animal efficacy data are present.
- Selectivity profile: Selectivity for PTH2R over PTH1R and other related receptors is not fully characterized in the available literature beyond the reported EC50 comparison with PTH.
- Endogenous physiological role: The role of endogenous TIP-39 in human or rodent neuroendocrine and pain systems is not resolved from the available literature.
- Pharmacokinetics and stability: No data on half-life, metabolic stability, blood-brain barrier penetration, or systemic pharmacokinetics are present in the available literature.
- Downstream signaling: The intracellular signaling cascade downstream of PTH2R activation by TIP-39 — including G protein coupling, second messenger effectors, and system-level outcomes — is not characterized in the available literature.
- Sequence verification: The sequence is reported from a single vendor catalog entry; cross-verification against the primary 1999 literature and sequence databases has not been performed in this authoring pass.
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.
Does the back half of TIP-39 act as the molecular key that unlocks PTH2R but not PTH1R?
If true, scientists could redesign just that tail region to make highly targeted drugs for pain or hormone disorders, while avoiding unwanted effects on bones or kidneys that come from activating the related receptor.
Could chemically locking TIP-39 into its receptor-binding shape make it more stable and potent as a drug?
Most natural peptides break down too fast to be useful medicines. If pre-shaping TIP-39 extends its lifetime in the body, it could become a viable drug for pain or stress disorders that would otherwise be impossible to develop.
Could TIP-39 act on the pituitary to turn down the body's overactive stress response?
If true, this could open a new drug target for PTSD and depression that works differently from all current treatments, potentially helping patients who do not respond to existing medications.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.7950819134712219 | openfold3-mlx |
| ranking score | 0.9278737306594849 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.924 | global PDE — lower = better |
| disorder | 0.334 | ! high disorder |
| chain pair ipTM (A, B) | 0.795 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 765s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
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
@peptide{pep10656,
sequence = {SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP},
target = {pth1r},
author = {peptidemodel},
year = {2026},
status = {computed}
}