Creating Molecules with Next-Generation Bio-Manipulation Technology to Prevent the Spread of Disease

Teruhiko Matsubara (Associate Professor, Department of Biosciences and Informatics)

The surface of cells is covered with glycans, which serve to protect the cell. However, some viruses and toxic proteins use these glycans as receptors, causing a variety of diseases. We are designing artificial molecules to help diagnose and treat such glycan-related diseases.

Molecules that block the interaction between surface receptors and viruses are expected to suppress the onset of various diseases, including infectious diseases and dementia. However, the structures of biologically active glycans are often complex, making their isolation from natural sources and artificial synthesis difficult. Therefore, we are designing artificial peptide molecules to function as substitutes for receptor glycans. A well-known example of using a substitute with the same physiological function is morphine. Morphine, a powerful analgesic, is a compound extracted from the poppy plant and is believed to mimic the action of enkephalin, a five-residue peptide in the body.

Peptides are structures of linked amino acids. Technology for their inexpensive mass production has been established, and they can also be expressed within cells through gene transfer. By artificially synthesizing random genes and incorporating them into the genome of an E. coli virus called a phage, we can prepare over 100 million types of artificial peptide sequences at once (this is called a phage library). From this library, we efficiently select peptides that bind to target viruses and other molecules (for a detailed explanation, click here: https://www.bionano-molec.org/backgrounds/phage-display/). The selected peptides can also be further subjected to "molecular evolution" to obtain molecules with high binding activity. We have so far discovered sequences that bind to influenza A virus and SARS-CoV-2 and have reported that they possess activity that inhibits viral infection.

The rapid diagnostic kits sold in pharmacies during the COVID-19 pandemic used immunochromatography with antibodies that bind to SARS-CoV-2. The mechanism involves linking colloidal particles (visible nanomaterials) to the antibodies. When the virus flows past, the antibodies recognize it, causing the colloidal particles to aggregate. This aggregation is designed to produce a color, making it visible as a band. These kits were originally used in medical settings primarily for influenza, but by substituting the appropriate antibodies, it is possible to create kits for diagnosing various infectious diseases.

However, rapid diagnostic kits are considered to have a sensitivity about 100 times lower than the polymerase chain reaction (PCR) method. Since PCR requires special reagents and equipment, it cannot be easily performed in medical settings or at home. Therefore, we are developing a highly sensitive electrochemical sensor with a sensitivity comparable to the PCR method (for a detailed explanation, click here: https://www.bionano-molec.org/research/flu-detection/). As devices for measuring blood glucose levels are a widespread application of electrochemical sensors, we expect that the realization of our sensor will lead to immediate practical use.

In life science research, we handle a variety of biomolecules, including proteins like enzymes and antibodies, as well as nucleic acids, lipids, and glycans. Research is conducted by placing these molecules in glass or plastic test tubes, but contact with the test tube walls can cause them to become inactivated, lower their effective concentration, and adversely affect the results.

This led us to a shift in thinking: "What if we didn't use test tubes at all?" We are now developing technology for containerless research (for a detailed explanation, click here: https://www.bionano-molec.org/backgrounds/acoustic-levitation/). The process is simple: we just "levitate the reaction solution in the air." To achieve this, we utilize the phenomenon of acoustic levitation.

We have reported that simply levitating a solution in the air provides efficient agitation, which improves the efficiency of organic synthesis through click reactions and enhances gene transfer. This method is also expected to significantly reduce plastic waste from experiments.

(Laboratory of Bio-molecular Chemistry website: https://www.bionano-molec.org/)