A Genetically Encoded, Phage-Displayed Cyclic-Peptide Library
A Genetically Encoded, Phage-Displayed Cyclic-Peptide Library
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DOI：
10.1002/anie.201908713
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发表时间：
2019-09-09
影响因子：
16.6
通讯作者：
Liu, Wenshe Ray
中科院分区：
文献类型：
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作者：
Wang, Xiaoshan Shayna;Chen, Peng-Hsun Chase;Liu, Wenshe Ray
环肽的生物活性优于线性肽，被认为具有作为治疗剂的巨大潜力。为了鉴定治疗靶点的环肽配体，噬菌体展示的肽文库已被广泛使用，其中通过半胱氨酸的共价缀合实现环化。为了解决与半胱氨酸缀合相关的缺点，我们发明了一种噬菌体展示技术，其中通过半胱氨酸和琥珀密码子编码的 N-ε-丙烯酰基-赖氨酸 (AcrK) 之间的邻近驱动迈克尔加成反应来环化其展示的肽。使用随机 6 聚体文库（其中肽通过半胱氨酸-AcrK 连接子在两端环化），我们证明了成功选择了 TEV 蛋白酶和 HDAC8 的有效配体。所有选定的环肽配体对其蛋白质靶标的亲和力比其线性对应物强 4 至 6 倍。我们相信这种方法将在药物发现中得到广泛的应用。
Superior to linear peptides in biological activities, cyclic peptides are considered to have great potential as therapeutic agents. To identify cyclic-peptide ligands for therapeutic targets, phage-displayed peptide libraries in which cyclization is achieved by the covalent conjugation of cysteines have been widely used. To resolve drawbacks related to cysteine conjugation, we have invented a phage-display technique in which its displayed peptides are cyclized through a proximity-driven Michael addition reaction between a cysteine and an amber-codon-encoded N-epsilon-acryloyl-lysine (AcrK). Using a randomized 6-mer library in which peptides were cyclized at two ends through a cysteine-AcrK linker, we demonstrated the successful selection of potent ligands for TEV protease and HDAC8. All selected cyclic peptide ligands showed 4- to 6-fold stronger affinity to their protein targets than their linear counterparts. We believe this approach will find broad applications in drug discovery.