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

点击翻译按钮获取中文摘要

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.