Random Peptide Library for Ligand and Drug Discovery
Random Peptide Library for Ligand and Drug Discovery
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用于配体和药物发现的随机肽库
DOI：
10.1007/978-94-007-6726-3_2-1
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Tai Kubo
中科院分区：
文献类型：
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作者：
M. Hirasawa;K. Takubo;H. Osada;S. Miyake;E. Toda;M. Endo;K. Umezawa;K. Tsubota;Y. Oike and Y. Ozawa;Tai Kubo
在古代，主要来自植物和动物的天然提取物被用于医疗或宗教目的。即使在现代药理学领域开始药物发现和开发之后，传统药物仍然受到合理的重视。此外，药物发现的现代方法得到了天然存在的配体和进攻和防御相关物质的资源和积累的知识的明显支持。其中，生物活性肽、肽毒素和抗体因其上级的靶点选择性而成功应用于治疗。然而，与小分子量药物相比，此类生物治疗剂具有中等至大分子量（> 500 Da）。尺寸最小化特别关注膜渗透性、在血液中的稳定性、抗原性和生产成本。十多年来，生物活性分子在其亲和力、稳定性和人源化方面已经被工程化并进一步改进，以使其适用于生物治疗。在这一章中，目前正在使用的两种方法来改善生物治疗药物进行了概述：基于免疫球蛋白的生物治疗药物的尺寸减小和非免疫球蛋白支架的利用。在这两种方法中，基于每个支架构建随机肽文库，并筛选具有感兴趣的生物活性的特异性结合剂（多肽）。一些编码进攻/防御或生殖相关蛋白质的基因在成熟蛋白质编码区经历了异常快速的氨基酸替换，而半胱氨酸框架和α/β结构是保守的，以维持分子支架。这种进化模式（称为加速进化）激发了利用
In ancient times, natural extracts that derived mainly from plants and animals were utilized for medical or religious purposes. Even after starting the drug discovery and development in the realm of modern pharmacological sciences, the traditional medicines are still reasonably valued. Moreover, the modern approaches for drug discovery are appreciably supported by the resources and the accumulated knowledge of naturally occurring ligands and the offense-and defense-related substances. Among them, bioactive peptides, peptide toxins, and antibodies have been successfully applied in therapy due to their superior target selectivity. However, such biotherapeutics have middle to large molecular weights (> 500 Da) in contrast to small molecular weight drugs. Size minimization is especially a concern for membrane permeability, stability in blood, antigenicity, and production costs. Biotherapeutic molecules have been engineered and further improved in terms of their affinity, stability and humanization for more than a decade to make them suitable for biotherapeutics. In this chapter, two approaches currently being used to improve biotherapeutics are overviewed: the size reduction of immunoglobulin-based biotherapeutics and the utilization of nonimmunoglobulin scaffolds. In both approaches, random peptide libraries are constructed based on each scaffold and screened for specific binders (polypeptides) with bioactivities of interest. Natural scaffolds that have been refined during long-term evolution are focused on. Some genes encoding offense/defense or reproduction-related proteins are known to undergo unusually rapid amino acid substitutions in the mature protein-coding regions, whereas the cysteine framework and α/β structures are conserved to maintain the molecular scaffold. This mode of evolution (called accelerated evolution) inspired the utilization of the