タンパク質作用面を認識する合成中分子の設計戦略

抄録

Developing clinically relevant synthetic agents that are capable of modulating protein-protein interactions (PPIs) has been recognized as a central goal in the Post-Genomic era. Specific control of the large and flexible PPI interfaces requires multivalent large agents. Mid-sized molecules provide a promising scaffold for designing PPI inhibitors, however, their large size often limits cell permeation, and the requirement of appropriate spatial distribution of many functional groups leads the issue of chemical tractability. In an effort to explore a new methodology of designing mid-sized PPI inhibitors to target intracellular targets, we have studied the strategy based on assembling small module compounds to create multivalent mid-sized agents. Herein, I describe three particular approaches based on the module assembly; metal-coordination-based ligand assembly, assembly of two modules for a pocket and a local surface, and intracellular assembly to generate an inhibitor in cells. These agents were shown to possess abilities to recognize targeted protein surfaces selectively and inhibit their PPIs in cells. This strategy may open a general approach that are applicable for regulation of intracellular PPIs by synthetic molecules.