Blood-vessel-tightening peptide fragment (CHEMBL313984 / FDIIW)

What this is

This is a short five-amino-acid research peptide (sequence FDIIW: Phe-Asp-Ile-Ile-Trp) cataloged in the ChEMBL bioactivity database under ID CHEMBL313984. It is not a drug, not a supplement, and has no clinical or cosmetic use — it is a structure–activity probe built around the C-terminal end of endothelin-1, the body's most powerful natural vasoconstrictor peptide. Researchers in the early 1990s synthesized variants of this region to learn which residues a small-molecule blocker would need to mimic in order to occupy the endothelin receptor.

History

Endothelin-1 was identified in 1988 as the most potent endogenous vasoconstrictor known, and its C-terminal hexapeptide His16-Leu-Asp-Ile-Ile-Trp21 was quickly recognized as the minimum fragment that retains receptor recognition (the ET-(16–21) fragment "discriminates between different endothelin receptors", Hiley et al., Br J Pharmacol, 1989). Doherty and colleagues at Parke-Davis carried out a systematic structure–activity scan of this hexapeptide in the early 1990s, including a mono-D-amino-acid scan that produced [D-His16]-ET(16–21) as the first peptide ET antagonist seed (Doherty et al., Bioorg Med Chem Lett, 1993). A companion paper in the same year extended the scan into a broader hexapeptide series and laid out the SAR rules that subsequent groups built on (Doherty et al., J Med Chem, 1993). FDIIW belongs to the truncation/substitution arm of that programme: His16 is replaced with phenylalanine and the Leu17 spacer is dropped, leaving a five-residue peptide that still carries the Asp-Ile-Ile-Trp "address" the receptor reads.

What it does

FDIIW binds the endothelin A receptor (ETA / EDNRA) — the receptor that drives the vasoconstrictor and proliferative effects of endothelin in pulmonary and systemic vascular smooth muscle. The ChEMBL entry records an IC50 of 200 nM for this peptide at EDNRA, meaning it occupies the receptor at sub-micromolar concentrations in a biochemical binding assay. It is a tool compound: its purpose is to map which side chains a competitive ETA blocker has to present, not to be administered. The clinically used drugs that grew out of this whole line of work — bosentan, ambrisentan, sitaxentan, macitentan — are small molecules, not peptides, but their pharmacophore is informed by exactly the C-terminal recognition motif this peptide samples.

Mechanism

Endothelin-1 is a 21-residue, two-disulfide peptide whose C-terminal "tail" (residues 16–21) docks into the orthosteric pocket of the ETA and ETB receptors. The Trp21 indole and the Asp18 carboxylate are the two anchors most often highlighted in SAR work on this region; alanine scans and unnatural substitutions at positions 16–17 swing the molecule between agonist, partial agonist and antagonist behaviour (reviewed in Warner, Cardiovascular Drug Reviews, 1994; Bagnato & Spinella in Endothelin Receptor Antagonists, Springer, 2001). FDIIW samples this motif with Phe substituted for the native His16 and the Leu17 hinge residue removed — a deliberate truncation to test whether the receptor will tolerate loss of the spacer and a non-basic aromatic at position 16. The 200 nM IC50 indicates the receptor still recognizes the truncated, Phe-bearing variant, though with lower affinity than longer or more elaborated analogs in the same series. Bulkier aromatic substitutions at the equivalent position — diphenylalanine, β-naphthyl-substituted glycine — went on to yield low-nanomolar dual ETA/ETB antagonists such as PD 142893 and PD 156252 (Cody et al., Med Res Rev / J Med Chem 1997 series).

Evidence

• Human: No human trials. This is a ChEMBL research ligand, not a drug candidate.
• Animal: No in-vivo data attached to this specific compound in the dossier; the broader Doherty hexapeptide series was profiled in isolated tissue and anaesthetised-animal preparations of the era.
• In vitro: IC50 = 200 nM at human EDNRA (ChEMBL CHEMBL313984). The value comes from the SAR campaign reported in Doherty et al., Bioorg Med Chem Lett, 1993 and Doherty et al., J Med Chem, 1993.

Related peptides

• Endothelin-1 — the parent endogenous 21-residue vasoconstrictor whose C-terminal His-Leu-Asp-Ile-Ile-Trp tail this peptide is derived from.
• EDNRA ligand CHEMBL273391 (FLDIIW) — the 6-mer Phe-Leu-Asp-Ile-Ile-Trp analog in the same Doherty series (IC50 18.4 µM); contrast with FDIIW shows the effect of the Leu17 deletion.
• EDNRA ligand CHEMBL317099 (FFDIIW) — a 6-mer with a second Phe substitution from the same SAR series.
• EDNRA ligand CHEMBL405599 (RDIIW) — the highest-affinity short pentapeptide in the cluster (IC50 4 nM), illustrating how a basic residue at position 16 changes ETA recognition.
• EDNRA ligand CHEMBL319660 (LDVIW) — another low-nanomolar (17 nM) pentapeptide variant from the same C-terminal scan.