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Chemical biology and structural development studies performed at The University of Tokyo during 1977-2020 are outlined chronologically. The studies are divided into three parts, i.e., (i) chemical biology of chemical carcinogenesis and molecular design of anti-tumor agents, (ii) structural development studies on biological response modifiers, and (iii) studies on so-called dramatype drug discovery focusing on pharmacological chaperones and protein knockdown-inducers. The first part describes analysis of DNA modification by Glu-P-1, which is a typical carcinogenic heterocyclic amine found in cooked foods, as well as molecular design of DNA-cleaving agents with anti-tumor properties. The second part deals with structural development studies of nuclear receptor ligands and various biological response modifiers derived from thalidomide, including the ligand superfamily concept and the multi-template strategy. The third part describes pharmacological chaperones that should be useful for the treatment of protein misfolding diseases, including Niemann-Pick type C disease and retinitis pigmentosa, and a protein knockdown strategy aimed at degradation of neurodegenerative-disease-causing polyglutamic aggregative proteins.

Nucleic acids are expected as novel effective medicines, although they require a drug delivery system (DDS). Complexes of nucleic acids with cationic liposomes and cationic polymers have been mainly used as DDS for clinical use. However, most cationic complexes have disadvantages such as strong cytotoxicity and low biocompatibility. We previously found that a plasmid DNA (pDNA) complex coated with biodegradable γ-polyglutamic acid (γ-PGA) provided adequate gene expression without cytotoxicity. Based on these results, we developed a new DDS (multi-functional Nano-device) of pDNA using biodegradable polyamino acids. A typical cationic polyamino acid, poly-L-lysine (PLL), was complexed with pDNA. The binary complexes, however, showed low gene expression and high cytotoxicity. Gene expression was enhanced by addition of poly-L-histidine (PLH) to the binary complexes. PLH can increase endosome escape of the complexes by inducing pH-buffering effects. The quaternary complexes (pDNA-PLL-PLH-γ-PGA complexes) exhibited high gene expression and low cytotoxicity. Furthermore, we used dendrigraft poly-L-lysine (DGL) instead of PLL and PLH to enhance gene expression. DGL had sterically congested cations and was biodegradable. The ternary complexes (pDNA-DGL-γ-PGA complexes) exhibited markedly high gene expression and low cytotoxicity. The pDNA-DGL-γ-PGA complexes also had high gene expression in the marginal zone (rich dendritic cells) of the spleen after intravenous injection into mice. These results indicate that pDNA-DGL-γ-PGA complexes may be useful as vaccine vectors. Therefore we prepared a novel malaria DNA vaccine using Plasmodium yoelii GPI8p-transamidase-related protein pDNA (PyTAM). The PyTAM-DGL-γ-PGA complexes markedly improved survival time of model mice infected with malaria.