REDISCOVERING AN ENDOTHELIN ANTAGONIST (BQ-123) - A SELF-DECONVOLUTING CYCLIC PENTAPEPTIDE LIBRARY

A ''self-deconvoluting'' cyclic pentapeptide library, designed to prod uce 82 944 head-to-tail-linked peptides in 48 vials, has been prepared . The mixture included amino acids found in a recently optimized endot helin antagonist, BQ-123, originally isolated from microbial sources b g Banyu investigators. Using a positional scan approach, the most pote nt of 12 residues at each of the four variable positions uniquely redi scovered 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 f ollowing values of relative potency: cyclo(L-Pro-D-Val-L-Leu-D-Trp-D-A sp) 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-T rp-D-Asp) = 0.1. This study reflects the first time that the positiona l scan approach has been applied to cyclic peptide libraries using a k nown target, Although no analogs more potent than BQ-123 were discover ed, our results provide verification of our synthetic methods for prep aring head-to-tail cyclic peptide libraries and also lend support to t he use of carefully designed sublibraries for the rapid elucidation of potential leads within a relatively constrained set of peptide macroc ycles.