Bone-signaling research peptide (CHEMBL2369886)

What this is

This is a research peptide derived from salmon calcitonin — a bone-active hormone secreted by the ultimobranchial gland of fish — and used as a tool to study the human calcitonin receptor (CALCR). It is one entry in a series of lactam-bridged calcitonin analogues designed to test whether a side-chain ring between residues 17 and 21 can stabilise the bioactive shape of the hormone and make it more potent (Taylor et al., Journal of Medicinal Chemistry, 2002). The stored 19-residue chain (CSNLSTCVLGKLSQELDKL) is only one of two chains in the active construct: in the full molecule it is joined by a lactam bridge between the Asp at position 17 and an ornithine in a second chain that carries the C-terminal segment of salmon calcitonin (ending in a C-terminal amide), and the native Cys1–Cys7 disulfide bond of the calcitonin family is preserved. None of this chemistry is visible in the raw one-letter sequence.

What it does

In binding assays this analogue behaves as a high-affinity, full agonist of the calcitonin receptor. Taylor and colleagues (2002) reported that it displaced [¹²⁵I]-salmon calcitonin from the human calcitonin receptor (the I1 splice variant expressed in HEK293 cells) with a Ki of 0.069 nM, and from native calcitonin receptor in rat brain membranes with an IC50 of 0.249 nM. In a CRE-luciferase reporter assay in human neuroblastoma cells expressing the same receptor, it stimulated signalling with an ED50 of 0.053 nM, about 2.2-fold more potent than salmon calcitonin itself (ChEMBL CHEMBL2369886, primary data from Taylor 2002). The calcitonin receptor is a class B G-protein-coupled receptor that couples primarily to Gαs/cAMP, and is expressed on osteoclasts and in the central nervous system — the same receptor that medical-grade calcitonins act through to inhibit bone resorption.

History

The compound comes from a 2002 design-concept paper by John W. Taylor's group at Rutgers, working with collaborators at Pharmacia (Taylor et al., J Med Chem 2002). The series asked whether placing an Asp at position 17 and a basic residue (Lys or Orn) at position 21 — and then closing a side-chain lactam ring between them — could lock the central α-helix of calcitonin into the conformation it adopts when bound to its receptor. In their analogues built on the human calcitonin scaffold, the bridge produced very large gains in both binding and signalling. In analogues built on the salmon calcitonin scaffold, where this 19-mer originates, the bridge produced more modest gains: salmon calcitonin already has a strongly helical core, so there is less room for conformational stabilisation to add potency. The paper used the contrast between the two scaffolds to argue for a new design rule for potent calcitonin analogues.

Evidence

• Human: No clinical evidence. This is a research-grade pharmacology ligand catalogued in ChEMBL; it has not been studied in humans.
• In vitro: Ki = 0.069 nM at the human calcitonin receptor (I1 isoform, HEK293, [¹²⁵I]-sCT displacement); ED50 = 0.053 nM in a CRE-luciferase functional assay in human neuroblastoma cells expressing the same receptor; about 220% the potency of salmon calcitonin in the same assay (Taylor 2002).
• Animal: IC50 = 0.249 nM at native calcitonin receptor in rat brain membranes; about 150% the affinity of salmon calcitonin in the same preparation (Taylor 2002). No whole-animal pharmacology reported for this specific analogue in the cited work.

Mechanism

The calcitonin receptor (CALCR) is a class B (secretin-family) G-protein-coupled receptor whose canonical signalling output is cAMP via Gαs, with secondary coupling to phospholipase C and intracellular calcium (reviewed by Naot, Musson and Cornish, Physiological Reviews 2019). Salmon calcitonin and its analogues bind in the classic two-domain mode of class B GPCRs: the C-terminal half of the peptide docks into the receptor's extracellular domain, while the N-terminal half — including the Cys1–Cys7 disulfide ring carried by this 19-mer — engages the transmembrane bundle to drive receptor activation. The design rationale of the Taylor 2002 series is that an i, i+4 lactam bridge between Asp17 and a basic residue at position 21 stabilises an α-helical turn in the central region of the peptide, the same region that crystallographic and photoaffinity studies have placed at the receptor's extracellular-domain interface.

Known effects

• CALCR agonism — Sub-nanomolar full agonist at the human calcitonin receptor in vitro (Taylor 2002).
• Cross-species activity — Retains high affinity at the rat-brain calcitonin receptor, consistent with the highly conserved binding mode of calcitonins across mammals (Taylor 2002).

Related peptides

• CALCR ligand CHEMBL2369895 (18-mer) — sister analogue from the same Taylor 2002 series, one residue shorter at the C-terminus of the stored chain.
• CALCR ligand CHEMBL2369907 (30-mer) — longer salmon-calcitonin-based analogue from the same series.
• CALCR ligand CHEMBL2369915 (29-mer) — another sister analogue from the same series, with a different position-17/18 substitution pattern.