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

Arno F. Spatola, Yvon Crozet, Damiane DeWit, Masashi Yanagisawa

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 amine 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 amine 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.

Original languageEnglish (US)
Pages (from-to)3842-3846
Number of pages5
JournalJournal of Medicinal Chemistry
Issue number19
StatePublished - Sep 13 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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