Blood-vessel-narrowing blocker (LKIIW / CHEMBL2370255)
A tiny lab-made peptide that blocks the receptor controlling blood vessel tightening; used only as a research tool to study cardiovascular biology.
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
LKIIW is a synthetic five-amino-acid research peptide that binds to the endothelin type-A receptor (ETA, gene name EDNRA) — a cell-surface receptor found predominantly on vascular smooth muscle. It was identified through a Parke-Davis medicinal chemistry program that mapped which parts of the endothelin-1 peptide are responsible for receptor binding. The parent compound of the series, PD 142893 (full sequence Ac-DDip-Leu-Asp-Ile-Ile-Trp), was the first potent combined ETA/ETB antagonist characterised from this C-terminal hexapeptide scaffold, and LKIIW is a pentapeptide variant from the same structure–activity study (Cody and colleagues, Journal of Medicinal Chemistry, 1995).
History
Endothelin-1 was discovered in 1988 and recognized quickly as one of the most potent vasoconstrictors then known. After the two endothelin receptor subtypes — ETA and ETB — were cloned in 1990–1991, pharmaceutical groups began searching for selective antagonists. Parke-Davis researchers focused on the C-terminal six-residue segment of endothelin-1 (positions 16–21, His-Leu-Asp-Ile-Ile-Trp) as a minimal pharmacophore capable of supporting antagonist activity. By replacing His16 with the bulky non-natural D-amino acid 3,3-diphenylalanine (DDip), Cody and colleagues produced PD 142893 — a low-nanomolar ETA/ETB dual antagonist — and then used systematic modifications of this hexapeptide scaffold to probe how each position contributes to potency and receptor-subtype selectivity (Cody and colleagues, J Med Chem, 1995). LKIIW is a five-residue variant from this campaign, retaining the C-terminal Ile-Ile-Trp motif identified as critical for receptor engagement.
What it does
LKIIW binds the ETA receptor with an IC50 of 430 nM in a radioligand displacement assay (ChEMBL entry CHEMBL2370255; Cody and colleagues, J Med Chem, 1995). The ETA receptor couples to Gq/G11 proteins and is the primary mediator of endothelin-1's potent, long-lasting vasoconstriction in vascular smooth muscle. As a ligand at this site, LKIIW can compete with endothelin-1 for receptor occupancy. Its affinity is substantially weaker than the parent hexapeptide PD 142893, which achieves low-nanomolar potency at both ETA and ETB, reflecting the known contribution of the N-terminal DDip moiety and other positions to high-affinity binding (Cody and colleagues, J Med Chem, 1995). The C-terminal tryptophan residue is recognized as essential for ETA recognition in this scaffold — its removal abolishes receptor binding.
Evidence
- Human: No human studies. LKIIW is a research ligand characterised in receptor-binding assays only.
- Animal: No animal model data identified for this specific pentapeptide.
- In vitro: IC50 = 430 nM at the human ETA receptor (EDNRA) measured in a radioligand displacement assay (ChEMBL2370255; Cody and colleagues, J Med Chem, 1995).
Mechanism
ETA (EDNRA) is a seven-transmembrane Gq/G11-coupled GPCR expressed mainly on vascular smooth muscle cells. When endothelin-1 binds, it activates phospholipase Cβ via Gq, generating inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 releases Ca²⁺ from intracellular stores, and DAG activates protein kinase C; together these signals drive sustained smooth muscle contraction. Unlike the ETB receptor subtype, ETA shows minimal ligand-induced desensitisation, explaining the unusually prolonged vasoconstriction characteristic of the endothelin system. The C-terminal hydrophobic region of endothelin-1 — including the Ile-Ile-Trp motif at positions 19–21 — forms the primary receptor-contact surface, which is why the hexapeptide and pentapeptide series built around this region were explored as antagonist scaffolds (Cody and colleagues, J Med Chem, 1995). LKIIW retains this C-terminal motif while differing from PD 142893 in the N-terminal portion of the sequence, accounting for its reduced affinity relative to the parent compound.
Open questions
- Selectivity of LKIIW over the ETB receptor (EDNRB) has not been reported.
- No functional antagonism data (e.g., inhibition of ET-1-induced contraction) have been published for this pentapeptide specifically.
- Proteolytic stability in biological fluids has not been characterised for this variant.
▸full evidence table1 metrics
| metric | value | tool |
|---|---|---|
| IC50 | 430 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{pep10316,
sequence = {LKIIW},
target = {ednra},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}