초록/요약

Phosphodiesterases(PDEs) are a superfamily of enzyme that regulates cyclic nucleotide signaling with diverse physiological functions. They are drug targets for the treatment of various diseases including heart failure, depression, asthma, inflammation and erectile dysfunction. To obtain novel drug candidates for these diseases, we have applied structural chemoproteomics technoloy. It includes structure determination of complexes between PDEs and their inhibitors, design and construction of structural chemoproteomic library for PDEs. Lead generation by the screening of the library, and optimization of the lead. We now have highly potent inhibitors for PDE4 and lead compounds for other PDEs. Moreover during the course of these studies, we could determine the structures of PDE5 bound with drug molecules such as Viagra, Cialis and Levitra(Nature 425, Sep. 4, 2003) and PDE 4 bound with various inhibitors. In this presentation, we will present structural aspects of PDE proteins, design strategies for PDE inhibitors and progress of lead optimization.