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Rediscovering an Endothelin Antagonist (BQ-123):  A Self-Deconvoluting Cyclic Pentapeptide Library

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journal contribution
posted on 13.09.1996, 00:00 by Arno F. Spatola, Yvon Crozet, Damiane deWit, Masashi Yanagisawa
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 our synthetic methods for preparing head-to-tail cyclic peptide libraries and also lend support to the use of carefully designed sublibraries for the rapid elucidation of potential leads within a relatively constrained set of peptide macrocycles.