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

这项工作利用了Flexizyme(人工氨基酰化核酶)与体外翻译系统(“灵活”的体外翻译系统，FIT)相结合的潜力，导致了迄今最大和最大残基的核糖体掺入。简而言之，由芳香族低聚酰胺组成的折叠分子--具有强烈折叠构象的分子--最近被证明能够启动翻译，产生了第一个此类折叠-多肽杂交物。在我们目前的工作中，我们扩大了折叠分子的功能范围，并证明了螺旋结构的侧链修饰允许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一残基的掺入已经被证明。此外，对核糖体在翻译起始过程中对芳香族寡酰胺的耐受性感兴趣，我们推进了我们的研究，并探索了在翻译延伸过程中将这些非生物分子作为附件加入的可能性。我们的结果表明，将氨基酸残基与侧链上的折叠酶结合在一起，只要是七肽，是可行的。它首次证明了核糖体对这种大小残基的耐受性，并扩大了目前对翻译机制局限性的理解。上述研究为将Folamers引入到mRNA展示中以发现功能性Folamer-多肽杂交体铺平了道路。

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.