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Phage Selection of Cyclic Peptides for Application in Research and Drug Development

环肽 噬菌体展示 组合化学 平移(音频) 连接器 计算生物学 化学 化学空间 肽库 抗菌肽 化学生物学 生物化学 生物 药物发现 肽序列 计算机科学 基因 操作系统 缩放 古生物学 镜头(地质)
作者
Kaycie M. Deyle,Xiangxing Kong,Christian Heinis
出处
期刊:Accounts of Chemical Research [American Chemical Society]
卷期号:50 (8): 1866-1874 被引量:112
标识
DOI:10.1021/acs.accounts.7b00184
摘要

Cyclic peptides can bind to protein targets with high affinities and selectivities, which makes them an attractive modality for the development of research reagents and therapeutics. Additional properties, including low inherent toxicity, efficient chemical synthesis, and facile modification with labels or immobilization reagents, increase their attractiveness. Cyclic peptide ligands against a wide range of protein targets have been isolated from natural sources such as bacteria, fungi, plants, and animals. Many of them are currently used as research tools, and several have found application as therapeutics, such as the peptide hormones oxytocin and vasopressin and the antibiotics vancomycin and daptomycin, proving the utility of cyclic peptides in research and medicine. With the advent of phage display and other in vitro evolution techniques, it has become possible to generate cyclic peptide binders to diverse protein targets for which no natural peptides have been discovered. A highly robust and widely applied approach is based on the cyclization of peptides displayed on phage via a disulfide bridge. Disulfide-cyclized peptide ligands to more than a hundred different proteins have been reported in the literature. Technology advances achieved over the last three decades, including methods for generating larger phage display libraries, improved phage panning protocols, new cyclic peptide formats, and high-throughput sequencing, have enabled the generation of cyclic peptides with ever better binding affinities to more challenging targets. A relatively new cyclic peptide format developed using phage display involves bicyclic peptides. These molecules consist of two macrocyclic peptide rings cyclized through a chemical linker. Compared to monocyclic peptides of comparable molecular mass, bicyclic peptides are more constrained in their conformation. As a result, they can bind to their targets with a higher affinity and are more resistant to proteolytic degradation. Phage-encoded bicyclic peptides are generated by chemically cyclizing random peptide libraries on phage. Binders are identified by conventional phage panning and DNA sequencing. Next-generation sequencing and new sequence alignment tools have enabled the rapid identification of bicyclic peptides. Bicyclic peptide ligands were developed against a range of diverse target classes including enzymes, receptors, and cytokines. Most ligands bind with nanomolar affinities, with some reaching the picomolar range. To date, several bicyclic peptides have been positively evaluated in preclinical studies, and the first clinical tests are in sight. While bicyclic peptide phage display was developed with therapeutic applications in mind, these peptides are increasingly used as research tools for target evaluation or as basic research probes as well. Given the efficient development method, the ease of synthesis and handling, and the favorable binding and biophysical properties, bicyclic peptides are being developed against more and more targets, ever increasing their potential applications in research and medicine.
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