Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides
Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides
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DOI：
10.1021/cb700233t
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发表时间：
2008-02-01
影响因子：
4
通讯作者：
Suga, Hiroaki
中科院分区：
文献类型：
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作者：
Goto, Yuki;Ohta, Atsushi;Suga, Hiroaki
起始密码子决定翻译起始事件仅从甲硫氨酸开始。我们在这里报告了一种新的技术，重新编程的起始事件，其中各种氨基酸和那些轴承N-α-酰基基团可以用作肽合成的引发剂。该技术建立在遗传密码重编程的概念上，其中甲硫氨酸从翻译系统中耗尽，起始密码子重新分配给所需的氨基酸。我们已经将该技术应用于合成由生理稳定键封闭的抗肿瘤环肽G7- 18 NATE，并且还将其扩展到具有各种环尺寸的其类似物的定制合成。值得注意的是，环化在前体线性肽翻译时自发发生。为了证明该方法的实用性，我们还制备了由160个不同mRNA命名的小环状肽文库。因此，该技术提供了一种新的手段来制备广泛的体内相容的环肽文库，用于发现针对各种治疗靶点的肽药物候选物。
The initiation codon dictates that the translation initiation event exclusively begins with methionine. We report here a new technology to reprogram the initiation event, where various amino acids and those bearing N-alpha-acyl groups can be used as an initiator for peptide synthesis. The technology is built upon the concept of genetic code reprogramming, where methionine is depleted from the translation system and the initiation codon is reassigned to the desired amino acid. We have applied this technology to the synthesis of an antitumor cyclic peptide, G7-18NATE, closed by a physiologically stable bond, and it is also extended to the custom synthesis of its analogues with various ring sizes. Significantly, cyclization occurs spontaneously upon translation of the precursor linear peptides. To demonstrate the practicality of this methodology, we also prepared a small cyclic peptide library designated by 160 distinct mRNAs. Thus, this technology offers a new means to prepare a wide array of in vivo compatible cyclic peptide libraries for the discovery of peptidic drug candidates against various therapeutic targets.