Blood-vessel-tightening peptide fragment (LDIIY / CHEMBL2370254)

What this is

This card describes a five-amino-acid research peptide with the sequence Leu-Asp-Ile-Ile-Tyr (LDIIY), catalogued in ChEMBL as CHEMBL2370254 and tested as a ligand at the endothelin A receptor (EDNRA). It is not a drug. It is a small, weakly potent fragment used in early structure–activity work on the endothelin system — the same body of work that eventually produced the clinical endothelin receptor antagonists used today for pulmonary arterial hypertension. The peptide is closely related to the natural C-terminal "business end" of endothelin-1, with the terminal tryptophan replaced by tyrosine.

History

Endothelin-1 (ET-1), a 21-residue peptide and one of the most potent vasoconstrictors known, was discovered by Yanagisawa and colleagues in 1988. Soon after, medicinal chemists realised that the hydrophobic C-terminal hexapeptide of ET-1 — His-Leu-Asp-Ile-Ile-Trp (residues 16–21) — was sufficient to retain receptor binding, and that this fragment could be used as the starting point for designing peptide antagonists. The Parke-Davis group led by William L. Cody developed a series of hexapeptide antagonists around this scaffold, the best-known being PD 142893 (Ac-DDip16-Leu-Asp-Ile-Ile-Trp21), a dual ETA/ETB antagonist described in detail by Cody and colleagues (J. Med. Chem. 1995). The LDIIY pentapeptide sits inside that exploration: a further-truncated analog of the conserved -Leu-Asp-Ile-Ile-Trp- pharmacophore, with the C-terminal Trp swapped for Tyr to probe the contribution of the indole side chain to receptor binding.

What it does

LDIIY is a competitive ligand at the endothelin A receptor — a G protein-coupled receptor expressed mainly on vascular smooth muscle, where the natural ligand ET-1 drives vasoconstriction and cell proliferation through Gq-coupled phospholipase C signalling (reviewed in Davenport et al., Pharmacol. Rev. 2016). The pentapeptide reproduces the conserved hydrophobic C-terminal motif of ET-1 but binds far more weakly than the full peptide, because the upstream residues (His16, the disulfide-stabilised core, the bicyclic loop) that ET-1 uses to anchor itself in the receptor pocket are absent. In ChEMBL it is recorded with an IC50 of 2200 nM at EDNRA — roughly four orders of magnitude weaker than ET-1 itself, which binds in the low picomolar range. The point of testing such fragments was not to find a drug but to map which side chains of the ET-1 tail are essential and which can be substituted; the LDIIY/LDIIW comparison contributes one data point to that map.

Mechanism

The conserved C-terminal "LDIIW" pharmacophore of ET-1 occupies a hydrophobic subpocket of the endothelin receptor, with the indole side chain of Trp21 making the most critical contact and the carboxylate of Asp17 forming a salt bridge to a basic receptor residue (Cody et al., J. Med. Chem. 1995; structural details later confirmed by cryo-EM of ET-1 bound to ETA and ETB, Nagiri et al., Nat. Commun. 2023). LDIIY substitutes a tyrosine hydroxyl-phenol for the tryptophan indole at the C-terminus, weakening the hydrophobic and stacking interactions that anchor the natural ligand. Removal of the His16 residue (present in the hexapeptide series including PD 142893) further reduces affinity. The combined effect — Trp→Tyr swap plus loss of the N-terminal His — explains the micromolar IC50 recorded for this fragment relative to the low-nanomolar affinities reported for the parent hexapeptide series.

The receptor itself, ETA, is a class A GPCR that couples primarily to Gαq/11 in vascular smooth muscle, driving IP3 generation, intracellular Ca²⁺ release, and sustained contraction. ETA is the receptor subtype targeted (selectively or non-selectively) by every approved endothelin receptor antagonist drug.

Evidence

• In vitro: A single quantitative binding measurement is on record for this fragment — IC50 = 2200 nM at EDNRA, deposited in ChEMBL under CHEMBL2370254 and traced back to the Cody and colleagues SAR series (J. Med. Chem. 1995). No other independent measurements have been published for this exact pentapeptide.
• Animal: No animal studies have been reported with LDIIY as a discrete compound. The broader hexapeptide series from which it descends was characterised in vascular preparations and isolated tissue assays by the Parke-Davis group, but those experiments used PD 142893 and related hexapeptides, not this pentapeptide.
• Human: None. This is a research fragment that has never entered clinical development.

Regulatory status

• US / EU: Not a drug. Not approved for any indication. No investigational status.
• WADA: Not listed by name. The compound is a research reagent only.

For context, approved endothelin receptor antagonists — none of which are peptides, and none of which derive from this fragment series — include bosentan (Tracleer; non-selective ETA/ETB; FDA-approved 2001), ambrisentan (Letairis; ETA-selective; FDA-approved 2007), and macitentan (Opsumit; non-selective; FDA-approved 2013), all used for pulmonary arterial hypertension. These are small-molecule sulfonamides developed long after the hexapeptide SAR work, and they reach the same receptor through a different chemical scaffold.

Related peptides

• Endothelin-1 (ET-1) — the 21-residue endogenous vasoconstrictor and parent ligand from which LDIIY's C-terminal motif is derived.
• PD 142893 (Ac-DDip-Leu-Asp-Ile-Ile-Trp) — the hexapeptide dual ETA/ETB antagonist from the same SAR series; LDIIY is a truncated, tyrosine-substituted analog of its C-terminal portion.
• BQ-123 — a cyclic pentapeptide ETA-selective antagonist developed in parallel to the Cody linear series, used as a reference tool compound in endothelin pharmacology.