Blood-vessel-tightening receptor blocker (EDIIW / CHEMBL97470)
A tiny synthetic peptide that blocks the receptor for endothelin-1, the hormone that tightens blood vessels; 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
EDIIW is a synthetic five-residue peptide (Glu-Asp-Ile-Ile-Trp) built from the hydrophobic C-terminal region of endothelin-1, a hormone that causes blood vessels to constrict. It was studied as part of a Parke-Davis Pharmaceutical Research program in the 1990s aimed at converting the C-terminal tail of endothelin-1 into compact antagonists of endothelin receptors. EDIIW binds the endothelin A receptor (ETA, gene name EDNRA) with an IC50 of 25 nM, as recorded in ChEMBL (CHEMBL97470) from the structure-activity study by Cody and colleagues (Journal of Medicinal Chemistry, 1995). It has no clinical use or approved indication and is a pharmacological tool compound.
History
Endothelin-1 was reported in 1988 by Yanagisawa and colleagues as the first endothelium-derived contracting factor — a 21-amino-acid vasoconstricting peptide. Both endothelin receptor subtypes, ETA and ETB, were cloned in 1990. Early drug-discovery work identified that the C-terminal hexapeptide of endothelin-1 (residues His16–Leu17–Asp18–Ile19–Ile20–Trp21) retained biological activity and could serve as a scaffold for antagonist design.
Chemists at Parke-Davis replaced His16 with the bulky non-natural amino acid 3,3-diphenylalanine (D-Dip), producing PD 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp), a dual ETA/ETB antagonist with low nanomolar affinity at both receptor subtypes. EDIIW is a five-residue variant explored in that same SAR campaign. The 1995 paper by Cody and colleagues (10.1021/jm00015a003) describes how modifications of the N-terminal residue at position 16 influenced subtype selectivity, with the goal of developing ETB-selective antagonists from the parent ETA/ETB dual scaffold.
What it does
EDIIW binds the endothelin A receptor (EDNRA), a receptor expressed on vascular smooth muscle cells that, when activated by endothelin-1, triggers potent vasoconstriction and promotes smooth muscle cell growth. As a fragment derived from an endothelin antagonist scaffold, EDIIW is used as a research probe to map how the C-terminal portion of hexapeptide antagonists contacts the ETA binding pocket. The parent compound PD 142893 was shown to act as a functional antagonist of ET-1 activity both in cell-based and in vivo systems (Cody and colleagues, 1995). EDIIW itself has not been evaluated as a standalone therapeutic agent.
A notable pharmacological liability of this peptide class was poor protease stability: PD 142893 had a half-life of less than 20 minutes in rat intestinal perfusate, limiting interest in the unmodified hexapeptide series as oral drug candidates (Cody and colleagues, 1995).
Evidence
- Human: No human trials. EDIIW is a research ligand with no clinical development record.
- Animal: Not reported as an independent compound. The parent hexapeptide scaffold (PD 142893) was evaluated in rat vascular models as part of the Parke-Davis SAR program (Cody and colleagues, 1995).
- In vitro: IC50 = 25 nM at EDNRA in radioligand displacement (ChEMBL CHEMBL97470; Cody and colleagues, J Med Chem, 1995).
Mechanism
EDNRA is a class A G protein–coupled receptor (GPCR) that couples primarily to Gq/G11 proteins. When endothelin-1 engages ETA on vascular smooth muscle cells, it activates phospholipase C, which generates inositol trisphosphate and triggers calcium release from intracellular stores, producing sustained vasoconstriction and smooth muscle proliferation.
The C-terminal region of endothelin-1 — particularly the Ile-Ile-Trp tripeptide at positions 19–21 — is critical for receptor engagement. Structure-activity studies on hexapeptide analogs of PD 142893 showed that modifications at position 16 (the N-terminal residue of the scaffold) could shift selectivity between ETA and ETB subtypes, while the Asp-Ile-Ile-Trp C-terminal portion was required for binding at either receptor (Cody and colleagues, 1995). EDIIW retains this essential C-terminal motif and achieves 25 nM potency at ETA.
Regulatory status
- US / EU: Not a drug. Research ligand only; no regulatory submissions.
- WADA: Not listed on the WADA Prohibited List.
Related peptides
The clinical successors to C-terminal hexapeptide endothelin antagonists are small-molecule drugs. Bosentan (FDA-approved 2001), ambrisentan (2007), and macitentan (2013) are approved for pulmonary arterial hypertension and work by blocking ETA and/or ETB signalling. A structurally distinct class of ETA-selective peptide antagonists — cyclic pentapeptides exemplified by BQ-123 — was developed in parallel during the same 1990s medicinal chemistry era and is also used as a research tool to probe the ETA binding site.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 25 nM | GPCRDB/ChEMBL |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.758 | global PDE — lower = better |
| disorder | 0.250 | fraction disordered |
| chain pair ipTM (A, B) | 0.867 | 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 | 313s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-23 |
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{pep10331,
sequence = {EDIIW},
target = {ednra},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}