Bone-building peptide from a cancer-linked protein (PTHrP 1-36)
A natural fragment of parathyroid hormone-related protein that stimulates new bone growth; also studied for its role in cancer-related high blood calcium. 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.
What this is
Human PTHrP-(1–36) is the first 36 amino acids of parathyroid hormone-related protein (PTHrP), a signaling molecule the body makes naturally. PTHrP was originally identified as the factor secreted by tumors that causes the high blood calcium seen in many cancers — a condition called humoral hypercalcemia of malignancy — but it turned out to also be a normal regulator of bone, calcium handling, and the development of many tissues. The 1–36 fragment is the active N-terminal piece: it binds and switches on the same bone-and-kidney receptor as parathyroid hormone (PTH), which is why researchers use it as a tool to study PTH/PTHrP biology and to probe whether PTHrP-based drugs can build bone. The stored sequence here (AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEI) is the linear human 1–36 form with free N- and C-termini — no acetyl cap, amidation, or fatty-acid modification.
History
PTHrP was identified in the late 1980s as the long-suspected tumor-secreted factor responsible for humoral hypercalcemia of malignancy — the protein that "looks like" PTH to bone and kidney even though it comes from cancer cells rather than the parathyroid gland. Once the protein was cloned, attention shifted to its N-terminal region, which shares enough homology with PTH(1–34) to activate the same receptor. Orloff and colleagues (Am J Physiol, 1992) showed that synthetic PTHrP-(1–36) bound and signaled through PTHrP receptors expressed on human squamous carcinoma cells — direct evidence that the 1–36 fragment was biologically active on the same cells whose tumors were causing the hypercalcemia syndrome. The Everhart-Caye and colleagues study (J Clin Endocrinol Metab, 1996) then administered synthetic PTHrP-(1–36) to humans and showed it was pharmacologically equipotent to PTH(1–34) on renal and calcium-regulatory endpoints, anchoring PTHrP-(1–36) as the relevant "natural" fragment for human pharmacology rather than the truncated PTHrP-(1–34) used in earlier comparisons.
What it does
In the body, PTHrP-(1–36) acts on the same receptor as parathyroid hormone — the PTH1 receptor (PTH1R) — which sits on bone-forming cells (osteoblasts) and on kidney tubule cells that handle calcium and phosphate. Activating that receptor raises blood calcium, reduces urinary calcium loss (anticalciuric activity), and — when the receptor is stimulated intermittently rather than continuously — pushes bone toward new formation rather than resorption. In human cell culture, PTHrP-(1–36) also acts on pancreatic β-cells, where it drives proliferation and supports insulin-producing function with induction of the cell-cycle regulators CDK2 and cyclin E (Guthalu Kondegowda and colleagues, Diabetes, 2010). These effects make it a research tool both for cancer-related calcium dysregulation and for skeletal anabolic biology — the same biology that the FDA-approved PTHrP-(1–34) analog abaloparatide (Tymlos) and the PTH-(1–34) analog teriparatide were built on.
Evidence
- Human: Everhart-Caye and colleagues (J Clin Endocrinol Metab, 1996) administered synthetic human PTHrP-(1–36) to human volunteers and reported pharmacological equipotency with PTH(1–34) for renal calcium and phosphate handling endpoints — the foundational human pharmacology study for the 1–36 fragment. No controlled efficacy trial of PTHrP-(1–36) for any clinical indication has been identified in the dossier sources.
- In vitro (cancer biology): Orloff and colleagues (Am J Physiol, 1992) characterized specific binding of radiolabeled PTHrP-(1–36) on human squamous carcinoma cell lines and on epidermal keratinocytes, demonstrating receptor-mediated signal transduction on tumor cells implicated in humoral hypercalcemia of malignancy.
- In vitro (β-cell biology): Guthalu Kondegowda and colleagues (Diabetes, 2010) showed that PTHrP enhances proliferation and function of human β-cells through PTH1R, with associated induction of CDK2 and cyclin E expression.
- Receptor pharmacology context: Independent work on PTH1R ligands — including Hattersley and colleagues' analysis of binding selectivity for distinct PTH1R conformations (Endocrinology, 2016) and Sato and colleagues' comparison of intracellular signaling kinetics across PTH1R ligands (JBMR Plus, 2021) — places PTHrP-(1–36)'s biology in context against the synthetic PTH1R analogs teriparatide, abaloparatide, and long-acting PTH.
Mechanism
PTHrP-(1–36) is an agonist at PTH1R, a class B G-protein-coupled receptor (Gardella and colleagues, Pharmacological Reviews, 2015). The N-terminal residues of PTHrP and PTH share the segment that drives receptor activation, while the more C-terminal portion of the 1–36 fragment contributes high-affinity binding at the receptor's extracellular domain. Engagement of PTH1R couples primarily to Gαs/adenylyl cyclase, raising cytosolic cAMP and activating PKA-dependent transcriptional programs; the receptor also couples through Gαq/PLC pathways and modulates IP3-mediated calcium signaling, with sustained PTH1R stimulation modulating IP3 accumulation via cAMP "junctions" (Meena and colleagues, J Cell Sci, 2014). PTHrP-(1–36) and PTH(1–34) preferentially engage somewhat different active-state conformations of PTH1R — distinct R0/RG preferences that map onto differences in signaling duration after receptor internalization (Dean and colleagues, Mol Endocrinol, 2006; Hattersley and colleagues, Endocrinology, 2016; Sato and colleagues, JBMR Plus, 2021). These conformational and kinetic differences are believed to underlie why PTHrP-derived ligands and PTH-derived ligands produce subtly different downstream skeletal effects, including the more selectively anabolic profile attributed to the PTHrP-analog abaloparatide. Gesty-Palmer and colleagues (Sci Transl Med, 2009) further showed that β-arrestin-biased agonism at PTH1R can promote bone formation independent of classical G-protein activation, broadening the mechanistic landscape PTHrP-(1–36) sits within. Receptor-level regulation in vivo also involves intracellular scaffolding partners such as Kindlin-2, which modulates PTH1R-driven bone formation in mouse osteoblasts (Fu and colleagues, Signal Transduction and Targeted Therapy, 2020). Detailed affinity values (Ki, IC50) for PTHrP-(1–36) at PTH1R are not reported in the dossier sources.
Known effects
- Calcium and phosphate handling — Equipotent to PTH(1–34) on renal calcium and phosphate endpoints in humans (Everhart-Caye and colleagues, 1996).
- Anticalciuric activity — Reduced urinary calcium loss in the same human pharmacological comparison (Everhart-Caye and colleagues, 1996).
- Receptor binding on tumor cells — Specific PTH1R binding and signaling on squamous carcinoma cell lines; mechanistic substrate of humoral hypercalcemia of malignancy (Orloff and colleagues, 1992).
- β-cell proliferation and function — Enhanced human β-cell growth with CDK2/cyclin E induction in vitro (Guthalu Kondegowda and colleagues, 2010); not validated in vivo or in human endpoint studies.
Safety signals
No systematic toxicology or adverse-event dataset specific to exogenous PTHrP-(1–36) has been extracted from the dossier sources beyond what the foundational human pharmacology study reported. Aggregate safety understanding of the receptor target PTH1R — including the rodent thyroid C-cell signal that anchored the original teriparatide label and the hypercalcemia-handling considerations that apply to all PTH1R agonists — derives from work on the approved analogs teriparatide and abaloparatide rather than from PTHrP-(1–36) itself.
Regulatory status
- US (FDA): Not approved. PTHrP-(1–36) is a research peptide; no marketing authorization for any indication.
- EU (EMA): Not assessed.
- Related approved drugs at the same receptor: Abaloparatide — a synthetic PTHrP-(1–34) analog, brand name Tymlos — and teriparatide — recombinant human PTH-(1–34) — are FDA-approved for osteoporosis and act at the same PTH1 receptor as PTHrP-(1–36).
Open questions
- Controlled efficacy in humans. The published human pharmacology of PTHrP-(1–36) establishes equipotency to PTH(1–34) on calcium/phosphate endpoints, but a definitive controlled efficacy trial for any clinical indication (e.g., osteoporosis) has not been identified in the dossier sources.
- β-cell translation. The in vitro evidence for human β-cell proliferation via PTH1R (Guthalu Kondegowda and colleagues, 2010) has not been translated into animal or human endpoint data in the dossier sources.
- Conformational selectivity in vivo. The R0/RG selectivity differences between PTHrP-(1–36), PTH(1–34), and engineered analogs like abaloparatide (Hattersley and colleagues, 2016; Sato and colleagues, 2021) are mechanistically interesting, but the in vivo consequences of those differences for the native PTHrP-(1–36) ligand — as opposed to the engineered analogs — are not fully mapped.
Related peptides
- Abaloparatide (Tymlos) — synthetic PTHrP-(1–34) analog, FDA-approved for osteoporosis; closest PTHrP-family clinical drug. (Plain text — internal card id not verified.)
- Teriparatide / PTH-(1–34) — recombinant human PTH-(1–34); the originally approved PTH1R anabolic and the comparator in essentially every PTHrP-(1–36) human pharmacology study.
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.
If the peptide only works on bone receptors, should we stop hoping it will also treat diabetes?
If the target is wrong, scientists can save years of effort and focus on making the peptide better at building bone, rather than chasing a metabolic effect that may not exist.
If doctors could apply the peptide directly at a fracture site, might it heal bones that refuse to mend on their own?
If true, patients with complex fractures or non-unions could avoid repeated surgeries and long disability by using a peptide-enhanced bone graft.
If cutting off those three arginines weakened the signal, would that reveal a new way to fine-tune bone drug strength?
If true, drug designers could dial bone drug potency up or down by adjusting that arginine cluster, creating safer or longer-lasting treatments.
If the peptide breaks down quickly, could that brief signal actually be better for building bone than a long one?
If true, doctors might get a bone drug that works with simple injections because its natural instability creates the exact on-off pattern bones need to grow.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.90975022315979 | boltz-2 |
| ranking score | 0.7706702947616577 | boltz-2 |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | colabfold_nvidia |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-25 |
▸citationbibtex
@peptide{pep10503,
sequence = {AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEI},
target = {glp-1r},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}