Perlman Zachary E, Bock Jonathan E, Peterson Jeffrey R, Lokey R Scott
Department of Systems Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115l, USA.
Bioorg Med Chem Lett. 2005 Dec 1;15(23):5329-34. doi: 10.1016/j.bmcl.2005.07.089. Epub 2005 Oct 6.
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 a 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.
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、D-氨基酸和脯氨酸残基的位置等参数可对环肽的构象产生显著影响，通过对其线性序列进行简单修饰就能获得结构多样的种类。我们合成了一个环肽文库，其中环大小、α-碳立体化学和脯氨酸位置各不相同。对产物的分析表明，一般来说七肽比六肽更容易环化，并且在这些组中，脯氨酸数量较多的支架环化产率明显低于脯氨酸数量较少的支架。基于这些支架样本集的分割-混合文库表明，一般而言，在决定环化效率方面，支架几何形状比侧链变化更为重要。这些概念被应用于非洲爪蟾卵提取物中肌动蛋白组装抑制剂的环二聚体变体的合成，得到了比原始支架效力更高的侧链变体。
