Geometric diversity through permutation of backbone configuration in cyclic peptide libraries
Geometric diversity through permutation of backbone configuration in cyclic peptide libraries
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DOI：
10.1016/j.bmcl.2005.07.089
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发表时间：
2005-12-01
影响因子：
2.7
通讯作者：
Lokey, RS
中科院分区：
文献类型：
--
作者：
Perlman, ZE;Bock, JE;Lokey, RS
环肽提供了改变支架几何形状和R基团功能的可能性。例如，诸如环大小和D-氨基酸和脯氨酸残基的位置的参数可以对环肽的构象具有显著影响，允许基于其线性序列中的简单修饰而获得结构多样的物质。我们合成了一个环状肽库，其中环的大小，α-碳立体化学，和脯氨酸的位置是不同的。对产物的分析表明，七肽一般比六肽更容易环化，并且在这些组中，具有更多数量的脯氨酸的支架比具有更少脯氨酸的支架以显著更低的产率环化。基于这些支架的Et样本集的分池库表明，一般来说，在决定环化效率方面，支架几何形状超过了侧链变化。这些概念被应用于合成的环二聚体变体的抑制剂肌动蛋白组件爪蟾卵提取物，产生侧链变体与改进的效力超过原来的支架。(c)2005爱思唯尔有限公司保留所有权利。
Cyclic peptides offer the possibility of varying both scaffold geometry and R-group functionality. For example, parameters such as ring size and the placement Of D-amino acid and proline residues can have a dramatic effect on the conformations of cyclic peptides, allowing access to structurally diverse species based on simple modifications in their linear sequences. We synthesized a cyclic peptide library in which ring size, alpha-carbon stereochemistry, and proline placement were varied. Analysis of the products showed that heptapeptides in general cyclized more readily than hexapeptides, and within these groups the scaffolds with a greater number of pralines cyclized with markedly lower yields than scaffolds with fewer pralines. Split-pool libraries based on Et sample set of these scaffolds showed that, in general, scaffold geometry outweighed side chains variation in determining cyclization efficiency. These concepts were applied to the synthesis of cyclodimeric variants of an inhibitor of actin assembly in Xenopus egg extracts, yielding side chain variants with improved potency over the original scaffold. (c) 2005 Elsevier Ltd. All rights reserved.