Middle molecular strategy: Creation of higher bio-functional molecules by integrated synthesis [Grant-in-Aid for Scientific Research on Innovative Areas]

Medium-sized biomolecules (molecular weight about 400-4000), such as natural products, glycans, peptides, and nucleic acid drugs, possess high chemical diversity and diverse biological activities.

In this research project, we will promote a middle-molecule strategy in three stages: development of novel biofunctional middle-molecules (A01), realization of highly efficient synthesis of biofunctional middle-molecules (A02), and evolution of reaction integration (A03).

Purpose of the Research Project

Medium-sized biomolecules (molecular weight about 400-4000), such as natural products, glycans, peptides, and nucleic acid drugs, have high chemical diversity and a variety of biological activities. They are also referred to as medium molecules, medium-sized molecules, or medium-sized molecules. Medium-sized molecules have great potential for higher biological functions due to the following characteristics. Because of their large surface area compared to small molecules, they are capable of rigorous and diverse molecular recognition based on multi-point interactions with target proteins, both “lock-and-key” recognition in the binding pocket and recognition at the protein surface. Some molecules can also interact with multiple proteins simultaneously and dynamically regulate signal transduction. Some also have membrane permeability and oral activity.

However, intermediates are difficult to synthesize because of their complex structures and require many reaction steps, which has been an obstacle to their practical application. In this research project, therefore, we will realize highly efficient synthesis of bioactive intermediate molecules through an innovative synthetic strategy based on reaction integration. Furthermore, novel bioactive intermediates will be developed through new strategies such as functional integration.

Content of the Research Project

This research project will develop biofunctional intermediate molecules based on two strategies: efficient synthesis of bioactive natural products and synthesis of hybrid-type intermediate molecules through functional integration. Efficient synthesis of intermediate molecules by reaction integration will also be discussed.

In A01, efficient synthesis of biofunctional intermediates such as glycans, nucleic acids, peptides, and lipids will be studied. In addition, development of novel biofunctional intermediates by functional integration, i.e., conjugation of bioactive compounds and creation of novel biofunctional molecules with π-electron compounds, will be investigated.

In A02, we aim at highly efficient synthesis of bioactive intermediates such as complex natural products. In addition, reaction integration based on new concepts and technologies such as synthesis using living cells and chemoenzymatic synthesis will be studied.

In A03, students will develop continuous reaction processes using microflow synthesis and one-pot synthesis, as well as practical reactions for multi-step synthesis. Synthetic transformations enabled by microflow methods, such as ultrafast reactions with unstable reactive species, will also be investigated.

Expected Research Achievements and Scientific Significance

This research project aims to achieve efficient synthesis of complex intermediate molecules by realizing highly efficient processes through reaction integration. The intermediates have high potential as biofunctional molecules for pharmaceuticals and agrochemicals, leading to innovative drugs, diagnostics, and agrochemicals, such as effective immunostimulants, synthetic vaccines, selective anticancer drugs, and environmentally friendly agrochemicals.