Spatola A F, Crozet Y
Department of Chemistry, University of Louisville, Kentucky 40292, USA.
J Med Chem. 1996 Sep 13;39(19):3842-6. doi: 10.1021/jm9604078.
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.
已制备了一个“自解卷积”环状五肽文库，该文库设计用于在48个小瓶中产生82,944个首尾相连的肽。混合物中包含了最近优化的内皮素拮抗剂BQ-123中的氨基酸，BQ-123最初是由Banyu研究人员从微生物来源分离得到的。使用位置扫描方法，在四个可变位置中的每个位置上最有效的12个残基中，唯一地重新发现了BQ-123序列或环（L-脯氨酸-D-缬氨酸-L-亮氨酸-D-色氨酸-D-天冬氨酸）。对四种最有效的氨基酸组合进行重新合成，得到了以下相对效价：环（L-脯氨酸-D-缬氨酸-L-亮氨酸-D-色氨酸-D-天冬氨酸）或BQ-123 = 1.0，环（L-脯氨酸-D-脯氨酸-L-亮氨酸-D-色氨酸-D-天冬氨酸）= 0.0，环（L-脯氨酸-D-脯氨酸-L-色氨酸-D-色氨酸-D-天冬氨酸）= 0.0，环（L-脯氨酸-D-缬氨酸-L-色氨酸-D-色氨酸-D-天冬氨酸）= 0.1。这项研究反映了位置扫描方法首次被应用于使用已知靶点的环状肽文库。虽然没有发现比BQ-123更有效的类似物，但我们的结果验证了我们制备首尾相连环状肽文库的合成方法，也支持使用精心设计的子文库在相对受限的肽大环集合中快速阐明潜在的先导化合物。
