ペプチドセレクションによる酵素ミミック創薬のための戦略

这项工作已经收获了柔性酶（人工氨基酰化核酶）与体外翻译系统（“柔性”体外翻译系统，FIT）耦合的潜力，导致核糖体整合迄今为止最大和最笨重的残基。简而言之，由芳香低聚酰胺组成的折叠分子——具有很强的折叠构象倾向的分子——最近被证明能够启动翻译，产生了第一个折叠分子-肽-杂合体。在我们目前的工作中，我们扩展了文件夹功能的曲目，并证明了螺旋结构的侧链修饰可以进入以前无法进入的化学和结构空间。核糖体引入的最大和最大的单残基的结合已被证明。此外，由于在翻译起始阶段核糖体对芳香寡胺的耐受性引起了我们的兴趣，我们进一步研究并探索了在翻译延伸期间将这些非生物分子作为附着物的可能性。我们的结果表明，氨基酸残基与侧链上的折叠体的结合，只要七肽，是可行的。它首次证明了核糖体对这种大小的残基的耐受性，并扩展了目前对翻译机制局限性的理解。上述研究为将折叠蛋白引入mRNA展示，发现功能性折叠蛋白-肽杂合体铺平了道路。

This work has harvested the potential of flexizymes (artificial aminoacylation ribozymes) coupled to an in vitro translation system (the “flexible” in vitro translation system, FIT), led to the ribosomal incorporation of the largest and bulkiest residues to date. Briefly, foldamers -molecules with a strong tendency to adopt a folded conformation- composed of aromatic oligoamides have been recently proven capable of initiating translation, yielding the first-of-their-kind foldamer-peptide-hybrids. In our current work, we expanded the repertoire of foldamer functionalities and have demonstrated that side-chain modification of the helical structures grants access to previously inaccessible chemical and structural space. The incorporation of both the bulkiest and largest single residues that have been introduced by the ribosome has been demonstrated. Additionally, intrigued by the ribosomal tolerance towards aromatic oligoamides during translation initiation, we advanced our investigations and explored the possibility of incorporating these abiotic molecules as appendages during translation elongation. Our results indicated that the incorporation of an amino acid residue with a foldamer on the side-chain, as long as a heptapeptide, is feasible. It demonstrates for the first time the tolerance of the ribosome towards residues of that size and expands the current understanding on the limitations of the translational machinery. The above studies have paved the way towards the introduction of foldamers into mRNA display for the discovery of functional foldamer-peptide hybrids.