Calcitonin receptor-binding research peptide (CHEMBL2369895)

What this is

This is an 18-residue research peptide — a truncated, modified piece of calcitonin used in the early 2000s by a Rutgers/Schering-Plough team as part of a program to redesign calcitonin into a more potent analogue. It is not a drug. It is one of many test compounds described in a published medicinal-chemistry study (Taylor and colleagues, Journal of Medicinal Chemistry, 2002), and it is catalogued in the public ChEMBL bioactivity database under the identifier CHEMBL2369895. The card exists because the compound has a measured high-affinity binding value against the calcitonin receptor (Ki = 0.023 nM, ChEMBL), which makes it useful as a reference ligand for receptor pharmacology and structural studies — not because anyone uses it therapeutically.

The stored sequence (CSNLSTCVLGKLSQELDK) corresponds to the N-terminal 1-18 region of salmon calcitonin with one substitution: aspartate replaces histidine at position 17 (H17D). Native calcitonins fold via a disulfide bond between Cys1 and Cys7, forming the conserved N-terminal ring that the cysteines in this sequence imply; that ring closure is not visible in the raw 18-letter string. The Asp17 residue is the design feature carried over from Taylor and colleagues' lactam-bridge series — in the full-length analogues described in that paper, an Asp at position 17 was paired with a Lys or Orn at position 21 to form a side-chain-to-side-chain lactam bridge that locked the helix. In this truncated 18-mer the partner residue at position 21 is absent, so the bridge itself cannot form within this fragment.

History

Calcitonin is a 32-residue peptide hormone secreted by the thyroid C-cells that lowers serum calcium and inhibits bone resorption. Salmon calcitonin (sCT) is roughly 30-50 times more potent than human calcitonin (hCT) at the human calcitonin receptor, and that activity gap has driven decades of medicinal-chemistry work trying to understand which structural features of the salmon sequence account for the difference and how to engineer them into the human sequence.

The compound on this card belongs to that lineage. Taylor and colleagues (Journal of Medicinal Chemistry, 2002) introduced a design concept based on side-chain-to-side-chain lactam bridges between residues 17 and 21 — an (i, i+4) constraint that pre-organises the central α-helix of calcitonin. Their lead analogue, cyclo(17-21)-[Nle8, Phe12, Asp17, Orn21, Tyr22]-hCT, was reported to be roughly 80-fold more potent than human calcitonin at the human calcitonin receptor and roughly 450-fold more potent than human calcitonin at rat-brain receptors in their assays (Taylor 2002). The 18-mer on this card is a structural relative of that series, carrying the Asp17 substitution on a salmon-calcitonin 1-18 backbone.

What it does

In intact calcitonins, the residues represented in this 18-mer make up the N-terminal "address-and-message" segment that engages the calcitonin receptor. The N-terminal disulfide loop (Cys1-Cys7) and the central α-helix (roughly residues 8-22 in full-length calcitonin) together drive receptor activation; the C-terminal residues (which this 18-mer lacks) contribute additional binding affinity (Taylor 2002).

The calcitonin receptor (CALCR) is a class B (secretin-like) G-protein-coupled receptor. When activated, it signals primarily through Gαs and raises intracellular cyclic AMP, with downstream effects on osteoclast function and renal calcium handling (Hay and colleagues, British Journal of Pharmacology, 2018 — secondary reference, see notes below).

The 0.023 nM value attached to this card is a single competition-binding affinity measurement reported in the ChEMBL database entry CHEMBL2369895. It is a receptor-binding number, not a measurement of biological efficacy in cells or animals, and it reflects the design intent of the Taylor 2002 series — pre-organised helices bind calcitonin receptor extremely tightly.

Mechanism

The calcitonin receptor (CALCR, gene CALCR) is a class B GPCR. Like other class B receptors it has a large extracellular N-terminal domain that captures the C-terminal half of its peptide ligand and a transmembrane bundle that the ligand's N-terminus then engages to trigger activation. Native calcitonins use exactly this two-step "address-and-message" mode: the disulfide-bridged N-terminal ring and the central helix sit in the transmembrane bundle, while the C-terminal residues anchor to the extracellular domain.

A distinguishing pharmacological feature of CALCR is that its ligand preference can be reshaped by association with receptor activity-modifying proteins (RAMPs). When CALCR forms a heteromer with RAMP1, RAMP2, or RAMP3, the resulting complex becomes a high-affinity amylin receptor (AMY₁, AMY₂, AMY₃) rather than a calcitonin receptor. This RAMP-dependent pharmacology is a defining feature of the calcitonin receptor family and is reviewed in the IUPHAR/BPS Guide to Pharmacology calcitonin receptors entry.

The design rationale behind the parent Taylor 2002 analogue — and the reason an 18-mer fragment of this kind is of interest — was that constraining the central helix into a pre-formed α-helical conformation through an (i, i+4) lactam bridge between positions 17 and 21 reduces the entropic cost of receptor engagement. Salmon calcitonin is intrinsically more helical in the relevant region than human calcitonin; by engineering an Asp17/Lys21 (or Orn21) lactam into the human sequence, Taylor and colleagues recovered a substantial fraction of the salmon-to-human activity gap (Taylor 2002).

Evidence

• Human: No human clinical evidence. This is a research compound, not a clinical candidate; no registered clinical trials are associated with the CHEMBL2369895 identifier.
• Animal: None directly attributable to this 18-mer fragment in the cited source. The parent (full-length) lactam-bridged analogue from Taylor 2002 was characterised in rat-brain receptor binding assays.
• In vitro: A single binding measurement of Ki = 0.023 nM at the calcitonin receptor is recorded for this compound in ChEMBL (CHEMBL2369895). The primary reference linking the series to the calcitonin receptor SAR is Taylor and colleagues (Journal of Medicinal Chemistry, 2002).

Known effects

• Calcitonin receptor binding — single in-vitro Ki measurement; reference ligand status (ChEMBL CHEMBL2369895).

No functional efficacy (cAMP, β-arrestin, in-vivo bone-resorption, or calcaemic) data have been located in the dossier for this specific 18-mer.

Regulatory status

• US / EU / WADA: Not approved, not investigational, not scheduled. This is a research-only peptide listed in ChEMBL as a bioactivity data point; it is not a drug. Approved calcitonin pharmaceuticals (e.g., calcitonin salmon, formerly marketed for osteoporosis and Paget's disease) are separate compounds — full-length 32-residue calcitonins — and are not interchangeable with this 18-mer fragment.

Related peptides

For context within the calcitonin receptor and related class B GPCR families, see other cards on the platform that share this receptor or ligand class. (No verified internal cross-references are included here because dossier coverage for related pep-ids was not established at draft time; the frontend will surface related cards via the shared CALCR target tag.)

Notes on sourcing

The dossier for this card contains a single primary reference: Taylor and colleagues (Journal of Medicinal Chemistry, 2002), the paper that describes the lactam-bridge design concept and the parent series from which this 18-mer is derived. The Ki value and ChEMBL identifier come from the public ChEMBL bioactivity database (entry CHEMBL2369895). General pharmacology of the calcitonin receptor (class B GPCR status, Gαs/cAMP signalling, RAMP-dependent amylin receptor formation) is supported by the IUPHAR/BPS Guide to Pharmacology and the secondary reference Hay and colleagues (British Journal of Pharmacology, 2018). No claims about clinical use, dosing, or therapeutic indications are made because none are supported by the source set.