Blood-vessel-narrowing peptide fragment (LDAIW / CHEMBL94907)

What this is

CHEMBL94907 (catalogued here with the sequence LDAIW) is a short synthetic peptide fragment derived from the C-terminal region of endothelin-1, the 21-amino-acid hormone recognised as one of the most potent vasoconstrictors in the human body. The five standard residues Leu-Asp-Ala-Ile-Trp (LDAIW) correspond to positions 17–21 of endothelin-1 and form the hydrophobic C-terminal tail responsible for engagement with the endothelin type A receptor (ETA, gene name EDNRA). It is a research ligand studied in the context of structure–activity relationship work on endothelin receptor antagonists; it has not been developed as a drug.

The stored sequence (LDAIW) represents the five standard amino acid residues of the full ChEMBL compound. In the actual tested molecule, an acetyl cap and a non-natural N-terminal aromatic residue (3,3-diphenylalanine, DDip) flank this core — neither modification is encoded in the stored single-letter sequence.

History

Endothelin-1 was isolated in 1988 by Yanagisawa and colleagues at the University of Tsukuba from porcine aortic endothelial cells and published in Nature as a novel potent vasoconstrictor peptide. Its extraordinary potency immediately prompted a search for antagonists. Early structure–activity studies established that the C-terminal hexapeptide of endothelin-1 — His-Leu-Asp-Ile-Ile-Trp (residues 16–21) — retains biological activity and constitutes the minimum fragment capable of engaging both receptor subtypes, ETA and ETB.

Medicinal chemists at Parke-Davis then explored systematic substitutions at the His16 position, replacing the native histidine with bulky D-amino acids to convert this agonist fragment into antagonists. This programme produced PD 142893 (Ac-D-Dip-Leu-Asp-Ile-Ile-Trp), a potent non-selective combined ETA/ETB hexapeptide antagonist with low nanomolar affinity at both receptor subtypes. The structure–activity relationships that generated PD 142893 and a series of ETB-selective variants — along with the structural role of the Leu-Asp-Ile-Ile-Trp C-terminal core — were reported by Cody and colleagues in the Journal of Medicinal Chemistry in 1995. CHEMBL94907, the compound catalogued here, is a closely related analog from that series in which Ile at position 19 is replaced by Ala, yielding the LDAIW C-terminal core, with a measured IC50 of 100 nM at the ETA receptor (Cody and colleagues, J. Med. Chem., 1995).

What it does

LDAIW (as part of the full CHEMBL94907 compound) acts as an antagonist at the endothelin type A receptor (EDNRA). The ETA receptor is a Gq/G11-coupled receptor expressed predominantly on vascular smooth muscle cells; when activated by endothelin-1, it triggers phospholipase C, raises intracellular calcium via IP3 and diacylglycerol, and drives sustained vasoconstriction. By competing with endothelin-1 at this binding site, C-terminal hexapeptide analogs of this class block the vasoconstrictor response. The C-terminal Trp residue and the Asp side-chain carboxylate within the LDAIW core contribute key interactions with the receptor's hydrophobic binding pocket and polar binding site, respectively — features identified as critical to receptor engagement in SAR studies of the endothelin C-terminal region (Cody and colleagues, 1995).

The Ile→Ala substitution at position 19 (relative to the native Ile-Ile-Trp motif of ET-1) is one of the modifications explored in the Cody 1995 SAR series to modulate receptor subtype selectivity between ETA and ETB.

Evidence

• Human: No human studies. CHEMBL94907 is a research ligand that has not entered clinical development.
• Animal: Not reported for this specific compound in the available literature.
• In vitro: IC50 = 100 nM at the human ETA receptor (EDNRA), as catalogued in ChEMBL (bioassay data sourced from Cody and colleagues, J. Med. Chem., 1995). The parent hexapeptide series (including PD 142893) achieved low nanomolar affinity at both ETA and ETB receptor subtypes in the same programme (Cody and colleagues, 1995).

Known effects

• ETA receptor antagonism — In vitro, IC50 = 100 nM (ChEMBL; Cody and colleagues, 1995)
• ETB receptor activity — Not reported for this specific compound; closely related analogs in the same series showed variable ETA/ETB selectivity depending on the N-terminal residue (Cody and colleagues, 1995)

Regulatory status

• US / EU: Not approved. Research compound only; not an IND-stage or clinical candidate.
• No registered trials on ClinicalTrials.gov for CHEMBL94907 or the LDAIW pentapeptide sequence.

Mechanism

CHEMBL94907 competes with endothelin-1 for binding at the ETA receptor (EDNRA), a Class A G-protein-coupled receptor that couples through Gq/G11 to activate phospholipase C, generate inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), and mobilise intracellular calcium in vascular smooth muscle (IUPHAR/BPS Guide to PHARMACOLOGY, ETA receptor entry). Within the hexapeptide antagonist class, the N-terminal residue at position 16 is the primary determinant of ETA vs. ETB subtype preference, while the C-terminal Leu-Asp-X-Ile-Trp scaffold (positions 17–21) provides the core binding energy. Replacing native His16 with D-diphenylalanine (D-Dip) or similar bulky aromatic D-amino acids converts the fragment from partial agonist to antagonist at both receptor subtypes (Cody and colleagues, 1995). The Ile→Ala substitution at position 19 present in LDAIW reduces steric bulk in the hydrophobic binding pocket and modulates receptor affinity relative to the parent compound PD 142893.

Open questions

• Subtype selectivity profile (ETA vs. ETB) for CHEMBL94907 specifically has not been reported in the available literature.
• Proteolytic stability of the LDAIW-containing hexapeptide under physiological conditions has not been characterised for this specific analog; hexapeptides in the broader series faced metabolic liability that limited further development.
• No structural data (crystal or cryo-EM) of this specific analog in complex with EDNRA.

Related peptides

The LDAIW core belongs to the endothelin C-terminal hexapeptide antagonist family studied in the early 1990s. The parent endogenous peptide is endothelin-1, whose C-terminal six residues (His16–Trp21) constitute the minimal receptor-binding pharmacophore. The reference ETA-selective peptide antagonist BQ123 — a cyclic pentapeptide (cyclo-[D-Asp-Pro-D-Val-Leu-D-Trp]) — acts at an overlapping site and is highly selective for ETA over ETB (IUPHAR/BPS Guide to PHARMACOLOGY). Clinically, the endothelin antagonist programme ultimately led to non-peptide drugs for pulmonary arterial hypertension: bosentan (dual ETA/ETB blocker, FDA-approved 2001) and ambrisentan (ETA-selective, FDA-approved 2007), both of which descended from the same receptor pharmacology that this peptide series helped define.