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flexizymes（人工氨酰化核酶）耦合到体外翻译系统（“灵活的”体外翻译系统，FIT）的潜力，导致核糖体掺入的最大和最笨重的残基。简而言之，最近已经证明由芳香族低聚酰胺组成的折叠体-具有采用折叠构象的强烈倾向的分子-能够引发翻译，产生第一种折叠体-肽-杂合体。在我们目前的工作中，我们扩展了折叠体功能的库，并证明了螺旋结构的侧链修饰赠款进入以前无法进入的化学和结构空间。已经证明了由核糖体引入的最大和最大的单个残基的掺入。此外，感兴趣的核糖体耐受性对芳香族低聚酰胺在翻译起始期间，我们推进了我们的调查，并探讨了将这些非生物分子作为附件在翻译延伸的可能性。我们的结果表明，在侧链上掺入一个氨基酸残基与一个折叠体，只要一个七肽，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。上述研究为将折叠体引入mRNA展示中以发现功能性折叠体-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.