Rediscovering an endothelin antagonist (BQ-123): A self-deconvoluting cyclic pentapeptide library

A “self-deconvoluting” cyclic pentapeptide library, designed to produce 82 944 head-to-tail-linked peptides in 48 vials, has been prepared. The mixture included amino acids found in a recently optimized endothelin antagonist, BQ-123, originally isolated from microbial sources by Banyu investigators. Using a positional scan approach, the most potent of 12 residues at each of the four variable positions uniquely rediscovered the BQ-123 sequence or cyclo(l-Pro-d-Val-l-Leu-d-Trp-d-Asp). Resynthesis of the four most potent amino acid combinations gave the following values of relative potency:  cyclo(l-Pro-d-Val-l-Leu-d-Trp-d-Asp) or BQ-123 = 1.0, cyclo(l-Pro-d-Pro-l-Leu-d-Trp-d-Asp) = 0.0, cyclo(l-Pro-d-Pro-l-Trp-d-Trp-d-Asp) = 0.0, and cyclo(l-Pro-d-Val-l-Trp-d-Trp-d-Asp) = 0.1. This study reflects the first time that the positional scan approach has been applied to cyclic peptide libraries using a known target. Although no analogs more potent than BQ-123 were discovered, our results provide verification of o...