Université Clermont Auvergne, CNRS, SIGMA Clermont, ICCF, F-63000 Clermont-Ferrand, France.
Biopolymers. 2019 Jun;110(6):e23273. doi: 10.1002/bip.23273. Epub 2019 Mar 21.
The design of linear peptoid oligomers adopting well-defined secondary structures while mimicking defined peptide primary sequences is a major challenge in the context of drug discovery. To this end, chemists have developed cis-inducing peptoid side chains to build robust polyproline type I helices. However, the number of efficient examples remains scarce and chemical diversity accessible through the use of these side chains is limited. Herein, we introduce an array of NCα-gem-dimethylated peptoid residues mimicking proteinogenic amino acids. Submonomer synthesis and block-coupling approaches were explored to access heterooligomers incorporating these novel types of side chains. NMR studies of monomer and trimer models showed that the NCα-gem-dimethylated groups exert complete cis control on the backbone amide conformation. Lastly, a preliminary molecular modeling study gave an insight into the preferred orientation of the substituents of the NCα-gem-dimethyl side chains relative to the peptoid backbone.
设计具有明确二级结构的线性拟肽寡聚物，同时模拟确定的肽一级序列，这在药物发现中是一项重大挑战。为此，化学家们开发了顺式诱导的拟肽侧链，以构建稳定的多聚脯氨酸 I 型螺旋。然而，有效的例子数量仍然很少，并且通过使用这些侧链可获得的化学多样性有限。在此，我们介绍了一系列模拟蛋白氨基酸的 NCα-偕二甲基化拟肽残基。探索了亚单体合成和块偶联方法来获得包含这些新型侧链的杂寡聚物。单体和三聚体模型的 NMR 研究表明，NCα-偕二甲基基团完全控制了骨架酰胺构象的顺式。最后，初步的分子建模研究深入了解了 NCα-偕二甲基侧链取代基相对于拟肽骨架的优选取向。
