Professor,
Graduate School of Pharmaceutical Sciences,
Kyoto University

Genomic information-converging Medicinal Chemistry Based on Chemical Proteomics


     Recent advance in genome science is providing us exponentially amplified drug targets. As such, there has been increasing upsurge in the development of innovative platform for genome/proteome-based drug discovery to facilitate the process thereof from a national standpoint. This project is intended to constitute a knowledge information infrastructure for a new frontier of chemogenomics-based medicinal chemistry beyond genomics and proteomics in fusion of genome science and chemistry. In order to embody the innovative axis for genome-lead drug discovery platform, we have been engaging the genomic information-converging approach in medicinal chemistry by integration of the following research programs.

1) Chemical characterization of drug targets based on comprehensive functional genomics
2) Downsizing of high molecular weight biologically active peptides/proteins using peptide-lead conformationally restricted templates for genome-lead drug discovery
3) Development of stereo-controlled synthetic process of peptide isosteres based on organo-metallic chemistry for "Peptide-Nonpeptide" link.
4) Chemical dissection of the aufbau principle of 7 transmembrane-G protein coupled receptor(7TM-GPCR) and daynamic outside-in signal transduction mechanism thereof
5) Reconstruction of 7TM-GPCR and pharmaceutical development thereof


     Herein, we summarize the recent investigations focusing on the development of highly specific CXCR4 antagonist, the receptor of which is relevant to several problematic diseases (cancer metastasis, AIDS, rheumatoid arthritis, etc.), as a practical application of the above strategy (Fig. 1). Of note, the highly specific CXCR4 antagonist, as a chemical probe, served to disclose the many physiological and pathological functions of CXCR4 including its important role for the formation of the dark zone and light zone appeared in germinal center of lymph node (Nature Immunology, 2004, 5: 943) A new method for the facile synthesis of membrane embedded peptides utilizing lipid bilayer-asisted chemical ligation has been also developed aiming at the chemical synthesis of CXCR4, which is classified to 7TM-GPCR family (Chem. Commun, 2004: 607).



Fig. 1. Downsizing and Nonpeptidylation of High Molecular Weight Peptides/Proteins by Conformationally-restricted Drug Discovery Templates :Practice in Peptidic CXCR4 Antagonist		Fig. 2. Towards the Chemical Synthesis of 7TM-GPCR