Genome/Proteome-lead Drug Discovery Based on Peptide/Protein Chemistry

基因组科学的最新进展应该提供指数放大的药物靶点。因此，在没有可靠的通用策略的情况下，开发创新平台以促进基于基因组/蛋白质组的药物发现过程的热潮日益高涨。我们致力于将有机金属化学应用于肽电子等排体的合成。在这个研究项目中，我们的“肽到非肽化学”与使用环肽作为生物活性肽/蛋白质和药物之间的桥接支架的几个先例相结合。值得注意的是，我们集中精力开发肽-先导构象限制模板，用于基因组/蛋白质组-先导药物发现。该方法包括以下有利特征：1）有效使用天然和非天然氨基酸作为手性构建块2）基于成熟肽化学的高度可靠的偏倚文库的有效构建3）使用NMR等容易鉴定活性构象4）通过使用烯电子等排体容易获得药物样（Lipinski）结构作为一个实施方案，我们研究了该策略，集中于其在14-肽CXCR 4拮抗剂的缩小和非肽化中的应用，CXCR 4拮抗剂的受体与几种有问题的疾病（癌症转移、AIDS、类风湿性关节炎等）相关，与CART（组成型活性受体技术）组合。针对7-跨膜G蛋白偶联受体家族CXCR 4的化学合成，开发了一种利用脂质双层辅助化学连接的膜包埋肽的简易合成新方法。总之，这些新方法将为建立创新的“基因组/蛋白质组主导的药物发现”平台提供新的途径。

Recent advance in genome science is supposed to provide exponentially amplified drug targets. As such, there has been increasing upsurge in the development of innovative platform to facilitate the genome/proteome-based drug discovery process, whereas there exists no reliable general strategy.We have engaged to apply organo-metallic chemistry to the synthesis of peptide-isosteres. In this research project, our "Peptide to Non-peptide Chemistry" was combined with the several precedents using cyclic peptides as bridging scaffolds between bioactive peptides/proteins and pharmaceutical drugs. Of note, we focused our efforts to develop peptide-lead conformationally restricted templates for genome/proteome-lead drug discovery. The method involves the following advantageous features :1)Effective Use of Natural & Unnatural Amino Acids as Chiral Building Blocks2)Efficient Construction of Highly Reliable Biased Library Based on Mature Peptide Chemistry3)Easy Identification of Active Conformation using NMR, etc.4)Easy Access to Drug-like(Lipinski) Structure by Alkene Isosteres UsageAs one embodiment, we examined this strategy focusing on its application to downsizing and non-peptidylation of a 14-peptide CXCR4 antagonist, the receptor of which is relevant to several problematic diseases (cancer metastasis, AIDS, rheumatoid arthritis, etc.), in combination with CART (Constitutively Active Receptor Technology). A new method for the facile synthesis of membrane embedded peptides utilizing lipid bilayer-assisted chemical ligation was also developed aiming at the chemical synthesis of CXCR4, which is classified to 7-transmembrane G-protein coupled receptor family. Taken together, these new methods will provide a new avenue to establish an innovative "Genome/Proteome-lead Drug Discovery" platform.