Side-chain-to-tail cyclization of ribosomally derived peptides promoted by aryl and alkyl amino-functionalized unnatural amino acids.
Side-chain-to-tail cyclization of ribosomally derived peptides promoted by aryl and alkyl amino-functionalized unnatural amino acids.
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DOI：
10.1039/c6ob00192k
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发表时间：
2016-06-28
影响因子：
3.2
通讯作者：
Fasan R
中科院分区：
文献类型：
--
作者：
Frost JR;Wu Z;Lam YC;Owens AE;Fasan R
报道了一种从核糖体衍生的多肽前体生产侧链至尾环肽的策略。两个遗传编码的非天然氨基酸，轴承无论是芳基或烷基氨基，他们的效率进行了研究，促进形成中型到大型肽大环通过内含肽介导的侧链到C-末端环化。虽然只观察到部分环化与前体蛋白含有对氨基苯丙氨酸，有效的肽大环化可以实现使用O-2-氨乙基-酪氨酸作为反应部分。方便的是，后者是在含叠氮基的对应物O-2-叠氮基乙基酪氨酸直接在E.大肠杆菌细胞。这种方法可以成功地应用于生产与模型靶蛋白链霉亲和素的结合亲和力增强的12聚体环肽，与无环对应物相比（KD：5.1 μM vs. 22.4 μM），从而证明了其对新型功能性大环肽的创造和研究的实用性。
A strategy for the production of side-chain-to-tail cyclic peptides from ribosomally derived polypeptide precursors is reported. Two genetically encodable unnatural amino acids, bearing either an aryl or alkyl amino group, were investigated for their efficiency toward promoting the formation of medium to large-sized peptide macrocycles via intein-mediated side-chain-to-C-terminus cyclization. While only partial cyclization was observed with precursor proteins containing para-amino-phenylalanine, efficient peptide macrocyclization could be achieved using O-2-aminoethyl-tyrosine as the reactive moiety. Conveniently, the latter was generated upon quantitative, post-translational reduction of the azido-containing counterpart, O-2-azidoethyl-tyrosine, directly in E. coli cells. This methodology could be successfully applied for the production of a 12mer cyclic peptide with enhanced binding affinity for the model target protein streptavidin as compared to the acyclic counterpart (KD: 5.1 μM vs. 22.4 μM), thus demonstrating its utility toward the creation and investigation of novel, functional macrocyclic peptides.