Designing biomolecules in interesting shapes and using them in therapeutic drugs
Hiroshi Abe , Associate Professor
Faculty of Pharmaceutical Sciences / Graduate School of Life Science (Pharmaceutical Sciences and Pharmacy)
High school : Kitahiroshima High School (Hokkaido)
Academic background : Hokkaido University Graduate School of Pharmaceutical Sciences
- Research areas
- Research areas: Bioorganic chemistry, synthetic organic chemistry, nucleic acid chemistry
- Research keywords
- Nucleic acid, fluorescence, drug discovery
What is your objective?
Figure 1 Nanosize molecular design
Figure 2 RNA interference by nano-structured RNA
Recently it has been discovered that RNA not only operates as an informational molecule, but has many other functions. One of these is the suppression of genetic expression, called RNA interference, for which a Nobel Prize was awarded in 2006. In 1989 also, a Nobel Prize was awarded for the discovery of RNA that has a catalyst function like that of the protein enzymes called ribozymes. Such discoveries have led to RNA-based drug discovery research. In particular RNA interference, which specifically suppresses genetic expression, has been of great utility to biotechnology and medical technology. To realize capabilities beyond RNA's original function, I aim to conduct my own nanosize molecular design and then to synthesize these molecules and utilize this technology as a new biomedical engineering technology.
Figure 1 shows RNA structures that do not occur naturally: dumbbell shapes, circular double strands, and 3- and 4-branch structures. RNA interference normally requires double-strand RNA, but this structure is problematic due to its extreme instability in vivo. An in vivo enzyme called exonuclease recognizes the end of the RNA and begins to break it down.
An endless circular translation phenomenon
It is possible to create interesting functions with molecular design as well. Messenger RNA codes amino acids and is translated into protein by ribosomes.Normal protein translation begins with the starting codon and finishes with the end codon. I wondered what would happen in the protein translation reaction if a circularly structured messenger RNA with no end codon was used as the template (Figure 3). Once the ribosome bonds with the RNA and begins synthesizing protein, there is no end, so in principle, protein synthesis would continue forever. Actually, we found that when we tried protein synthesis with a circular messenger RNA, we ended up with a long protein. We also found that this endless circular protein translation results in more protein being synthesized more efficiently than with ordinary straight messenger RNA.As shown in Fig. 2, dumbbell-shaped circular RNA has no end, and so is not broken down by the enzyme. Also, branched RNA, due to its nanosize branched structure, is sterically bulky, which prevents the enzyme from approaching. Both structural designs significantly increase RNA stability in vivo. However, when these nano-structured RNA enter the cell, they are slowly transformed into active form double-strand RNA by a special enzyme and display long-term suppression of gene expression.
Figure 4 Build-up method based on the concept of a ship in a bottle
Biopharmaceuticals use proteins and nucleic acids as constituents. Both are nanosized high-molecular substances. In medical applications, these molecules have weak points in that they do not enter cells easily and can trigger an immunological response. We know that low-molecular substances, on the other hand, have a high ability to permeate the cell membrane and are less likely to trigger an immunological response. So, as a new methodology, I aim to introduce low-molecular ingredients into cells and induce an organic chemical reaction to produce an active high-molecular pharmaceutical within the cell. Think of it like making a ship in a bottle (Figure 4), where small ingredients are placed in a bottle to build a large ship. Recently, I have demonstrated that it is possible to make high-molecular RNA from low-molecular RNA within the cell and suppress gene expression using this intracellular buildup method. I am progressing with research daily in the belief that this method can solve the problems associated with biopharmaceuticals.
A message to readers
Thinking theoretically to design new molecules is the best part of organic chemistry. Of course, things do not always go as originally planned, but that can actually result in the discovery of interesting phenomena. Getting to the root cause of why something happened can lead to the discovery of new fundamental principles. I believe the fun of creating new things lies in this type of research process. Come and join us and you’ll see!