Appetite & energy research tool (CHEMBL408257)
A lab-made peptide developed at Eli Lilly to help scientists study how the body controls appetite, energy use, and inflammation; used only as a research tool, not a medicine.
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
CHEMBL408257 is a synthetic cyclic peptide developed at Eli Lilly & Company as a laboratory tool for studying melanocortin receptors — a family of receptors that regulate appetite, energy balance, pigmentation, and inflammation. The compound was derived from human beta-melanocyte-stimulating hormone (β-MSH) and engineered to activate both the melanocortin-3 receptor (MC3R) and the melanocortin-4 receptor (MC4R) at subnanomolar concentrations. It is a research ligand, not a drug — it has been tested only in cell-based assays and has not entered human clinical development. Mayer and colleagues described the compound in the Journal of Medicinal Chemistry in 2005.
The platform stores the simplified four-letter sequence CEWC to represent the Cys-Glu-...-Trp-Cys disulfide core of this compound. The actual structure is a 9-residue cyclic peptide (Ac-D-Arg-c[Cys-Glu-D-His-D-Phe-D-Arg-Trp-Cys]-NH₂): N-terminally acetylated, C-terminally amidated, with four D-amino acid substitutions (D-Arg, D-His, D-Phe, D-Arg) and a disulfide bond bridging the two cysteine residues into a ring. None of these modifications — the D-amino acids, the acetyl cap, the C-terminal amide, or the ring-closing disulfide bond — appear in the four-letter stored sequence.
History
The melanocortin-4 receptor (MC4R) emerged in the late 1990s as a major target for anti-obesity drug discovery, after genetic knockout studies in mice showed that MC4R loss causes severe obesity. Researchers at Eli Lilly used human β-MSH (residues 5–22) as a starting scaffold, introducing a disulfide bridge to cyclize the backbone and systematically replacing L-amino acids with D-amino acids and truncating the sequence to improve potency and stability. Mayer and colleagues reported this compound series in 2005 as part of efforts to identify β-MSH-derived agonists with strong MC4R activity; CHEMBL408257 emerged from that series with potent agonism at both MC4R and MC3R.
What it does
CHEMBL408257 activates MC3R and MC4R in cell-based assays, triggering the production of cyclic AMP (cAMP) through Gs-coupled signaling — the same intracellular signal that natural melanocortin peptides produce when they bind these receptors. In functional assays at human receptors, it produced half-maximal cAMP responses at 0.68 nM at MC3R and 0.26 nM at MC4R, with relative efficacies of 87% and 96% respectively (Mayer and colleagues 2005). Binding affinity (Ki) was 33.8 nM at MC3R and 0.44 nM at MC4R, confirming that while the compound activates both receptors potently in functional terms, it binds MC4R considerably more tightly. Activity at MC5R was negligible (Ki > 500 nM), offering selectivity over this peripheral receptor subtype.
MC3R is expressed predominantly in the hypothalamus, where it contributes to the brain's management of energy availability — particularly the timing of feeding relative to caloric cues and the body's response to nutrient deficit. MC4R, in the same region, is the better-characterized driver of appetite suppression and energy expenditure. The compound's dual MC3R/MC4R activity makes it useful as a pharmacological comparator in studies aimed at disentangling the distinct roles of these two closely related receptors.
Evidence
- Human: No human trials. CHEMBL408257 is a research tool compound; all reported data are from cell-based pharmacology assays.
- In vitro: Near-full agonist at human MC3R (EC50 = 0.68 nM, relative efficacy 87%) and human MC4R (EC50 = 0.26 nM, relative efficacy 96%) in cAMP release assays; binding Ki = 33.8 nM at MC3R, 0.44 nM at MC4R, > 500 nM at MC5R (Mayer and colleagues 2005).
Mechanism
MC3R and MC4R belong to the melanocortin receptor family — five Gαs-coupled GPCRs (MC1R–MC5R) that share a common set of endogenous ligands derived from proopiomelanocortin (POMC): principally α-MSH, β-MSH, γ-MSH, and ACTH. CHEMBL408257 retains the His-Phe-Arg-Trp pharmacophore core that is conserved across POMC-derived ligands and required for activity across the melanocortin receptor subfamily. The cyclic disulfide scaffold locks this core in a conformation that favors receptor engagement, while D-amino acid substitutions at four positions protect the backbone from proteolytic degradation — a key design advantage over linear natural peptides.
Upon binding MC3R or MC4R, the compound activates adenylyl cyclase via Gαs, elevating intracellular cAMP. Mayer and colleagues identified ring size, ring conformation, and the aromatic character of the D-Phe residue within the disulfide ring as critical determinants of MC4R potency and selectivity in this scaffold series. The endogenous competitive antagonist for both receptors is agouti-related peptide (AgRP), which displaces melanocortin agonists from the binding pocket.
Known effects
- MC3R agonism (in vitro) — Near-full agonist (87% relative efficacy) at subnanomolar concentration; preclinical research tool only (Mayer and colleagues 2005).
- MC4R agonism (in vitro) — Higher potency at MC4R than MC3R (EC50 0.26 nM vs 0.68 nM); compound was developed primarily to study the β-MSH-derived MC4R scaffold (Mayer and colleagues 2005).
- MC5R sparing — Essentially inactive at MC5R (Ki > 500 nM).
Regulatory status
- US / EU: Not approved. Investigational research compound with no clinical development history.
- WADA: Not specifically listed; as an unapproved experimental peptide it falls under S0 (non-approved substances).
- Clinical trials: No trials registered on ClinicalTrials.gov for CHEMBL408257.
Related peptides
- Melanotan II — a cyclic α-MSH analog that also activates MC3R and MC4R; structurally related scaffold, more widely studied for pigmentation and appetite effects.
- β-MSH — the natural 22-residue precursor sequence from which CHEMBL408257 was derived.
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 ring shape of this peptide push the appetite receptor into a mode that keeps signaling longer than normal?
If true, this could point the way to appetite-suppressing drugs that stay effective longer without the body adapting and tuning them out. That would be a significant advance for people managing obesity or metabolic disease.
Could this peptide reduce harmful inflammation in the brain without changing a person's appetite?
If the anti-inflammatory effect kicks in at lower doses than the appetite effect, the peptide could be useful for brain inflammation conditions, such as those following stroke or severe infection, without causing unwanted metabolic side effects.
Does one acidic building block in the ring act like a pivot that aims the peptide at one receptor over another?
If this is true, chemists could swap that one building block to steer the peptide toward only the receptor relevant to energy balance, while leaving the pigmentation and other receptors alone. This could make for a cleaner drug with fewer off-target effects.
Can a four-amino-acid loop bind the appetite-regulating receptor on its own, without the extra pieces around it?
If the small cyclic core is enough to engage the receptor, chemists could build much simpler drugs targeting appetite and energy balance. Simpler molecules are usually cheaper to make and easier to turn into medicines.
Are the reversed amino acids responsible for making this peptide avoid receptors that control skin pigmentation and other unrelated functions?
If confirmed, drug designers could use this rule to tune selectivity across the whole melanocortin family. That would matter for anyone developing treatments for obesity or metabolic disease who needs to avoid side effects on skin or glands.
Could this small ring be attached to other therapeutic peptides to add appetite-suppressing activity as a second function?
If the ring can be transplanted, it opens a route to combination drugs that address obesity alongside another condition using a single molecule. That approach could simplify treatment for patients managing multiple metabolic problems at once.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| EC50 | 0.68 nM | GPCRDB/ChEMBL |
▸3-letter notation
▸recipeboltz-2 2.2.1
| parameter | value |
|---|---|
| model | boltz-2 2.2.1 |
| weights | — |
| hardware | vast_v100_32gb |
| mlx version | — |
| python | — |
| random seed | 1 |
| msa strategy | colabfold_local |
| runtime | — |
| predicted by | — |
| predicted at | 2026-05-22 |
▸citationbibtex
@peptide{pep10390,
sequence = {CEWC},
target = {mc3r},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}