Misawa Takashi
Division of Organic Chemistry, National Institute of Health Sciences.
Yakugaku Zasshi. 2022;142(10):1061-1066. doi: 10.1248/yakushi.22-00115.
Medium-sized peptides are expected as a next-generation drug discovery modality because they combine the properties of conventional small-molecule drugs and biopharmaceuticals. Nonetheless, peptides are easily degraded by digestive enzymes such as protease in the body, which could be problematic for the development of peptide-based drugs. To overcome such a problem, peptide-based foldamers containing non-proteinogenic amino acids or cyclized peptides have been reported. In addition, peptides must form stable secondary structures and their side chains should be correctly positioned to exert their bioactivity. In our lab, bioactive peptides have been developed based on regulation of secondary structures by introducing non-proteinogenic amino acids such as acyclic α,α-disubstituted amino acids (dAAs), cyclic dAAs, cyclic β-amino acids, and side-chain stapling. Based on these knowledges, I have been performing research on the development of bioactive peptides based on the secondary structural control of peptides as categorized in the following manner: (1) rational design of antimicrobial foldamers; (2) post-functionalization of helical peptides; (3) development of carrier peptides for intracellular delivery of siRNA utilizing the helical template peptides.
中等大小的肽有望成为下一代药物发现模式，因为它们兼具传统小分子药物和生物制药的特性。尽管如此，肽在体内容易被诸如蛋白酶等消化酶降解，这对于基于肽的药物开发可能是个问题。为了克服这一问题，已报道了含有非蛋白质氨基酸的基于肽的折叠体或环化肽。此外，肽必须形成稳定的二级结构，其侧链应正确定位以发挥其生物活性。在我们实验室，通过引入非蛋白质氨基酸（如无环α，α-二取代氨基酸（dAAs）、环化dAAs、环化β-氨基酸和侧链钉合）来调节二级结构，从而开发出了生物活性肽。基于这些知识，我一直在按照以下方式对基于肽二级结构控制的生物活性肽的开发进行研究：（1）抗菌折叠体的合理设计；（2）螺旋肽的后功能化；（3）利用螺旋模板肽开发用于细胞内递送siRNA的载体肽。
