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 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.
Spatola
A F
AF
Department of Chemistry, University of Louisville, Kentucky 40292, USA. afspat01@ulkyvm.louisville.edu
Crozet
Y
Y
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D016232:Endothelins / Q000037:antagonists & inhibitors*; D006801:Humans; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
D016232:Endothelins; D019151:Peptide Library; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)