Heretical thoughts spawn advanced technologies

– Rewriting the genetic code to develop new drug –
  • Professor Hiroaki Suga, Department of Chemistry

A bio-venture company, PeptiDream Inc. attracts attention as it continues to grow with innovative and unique technologies. Professor Hiroaki Suga, Department of Chemistry, School of Science is one of the co-founders of the company.

Technological studies to support the business venture on one hand, and the scientific research on the other - Professor Suga was interviewed on the link between the two and the history in which such technologies have been established.

“Nonstandard peptides”, a unique technology that won recognition by the major pharmaceutical companies

Figure 1

PeptiDream, a venture originated from the University of Tokyo, was listed on Mothers in June 2013. The shares were first traded on the next day of the initial public offering at 7,900 yen, rising to as high as 3.2 times the offer price of 2,500 yen, and instantly setting the company’s total market value at more than 130 billion yen.

The market has reacted to the following three points. First, the company’s unique drug development technology; second, joint research undertaken with major pharmaceutical companies in Japan and abroad based on that unique technology; and third, establishment of a business model to produce cash flow from the early stage of the joint research. PeptiDream is highly valued for its technology and business model. The company won Japan Bioventure Award in January 2013 and Business Model Award in February 2014.

PeptiDream was founded in July 2006 jointly by Professor Hiroaki Suga, then at Research Center for Advanced Science and Technology (Professor, Graduate School of Science, since April 2010), the University of Tokyo, who provided his drug development technologies, and Mr. Kiichi Kubota who plays the role of Chief Executive Officer. Professor Hiroaki Suga serves the company in the capacity of Outside Director engaged in promoting the technological enlightenment for the industry in Japan and abroad through such means as delivering lectures.

PeptiDream’s unique technology, also highly acclaimed by the business world, is a “nonstandard peptide” drug development technology. Naturally the company’s name is derived from this technology.

Peptides are chemical compounds of two or more naturally-occurring amino acids. They may also be called small-sized proteins. They act as hormones and signal transmitters of various kinds in living organisms playing important roles in vital activity. Having long attracted attention as possible candidates for new drugs for this reason, a number of barriers have prevented them from being realized. It is precisely because a possibility has been shown to overcome these issues that major pharmaceutical companies took note of Professor Suga’s “nonstandard peptides”.

Barriers that have prevented the realization of “nonstandard peptides”

Professor Suga explains why “nonstandard peptides” are “nonstandard”.

“Naturally-occurring peptides (normal type peptides) consist of combinations of only 20 kinds of amino acids (normal type amino acids). In contrast, amino acids with a special structure (nonstandard amino acids), such as D-amino acid and N-methyl amino acid, can be incorporated in our nonstandard peptides. They are called nonstandard peptides because they are made of nonstandard amino acids.”

Nonstandard peptides containing nonstandard amino acids have a potential to overcome the shortcomings of normal peptides. Normal peptides are quickly dissolved by the action of proteases in the blood once taken internally. Even if they escape being undissolved they may not be effective as drug. It is peptides containing nonstandard amino acids, or “nonstandard peptides” that can solve this problem. Nonstandard peptides with their unique structure avoid being dissolved by proteases and can permeate into cells. That is why they are counted on to function as drug.

Now, another question arises: Given such a high potential for the nonstandard peptides, everyone would scramble to make one. Why is it that to produce “nonstandard peptides” amounts to a unique technology?

A simple answer is that nonstandard peptides are very difficult to produce. Although it is possible to produce “nonstandard peptides” which incorporate nonstandard amino acids with conventional chemical technologies, just to link several tens of amino acids takes huge amount of work and costs. The reality is that use of such conventional technology to develop drug is far from a practical one.

Professor Suga’s technology also solves this problem. He has established a technology to efficiently produce many “nonstandard peptides” and to efficiently identify the ones with high possibility to function as drug. Not only that, but the technology allows as many as a trillion “nonstandard peptides” to be produced in a single test tube at a time, which goes to show its extraordinarily innovativeness.

Mechanism in which organisms produce peptides

Figure 2

Further, the method in which the “nonstandard peptides” are produced is another wonder. It, so to say, “hacks” the mechanism with which organisms produce peptides (proteins) from genetic information.

For us to understand the degree of ingenuity of the method, let us first look at the basic mechanism of organisms.

Genetic information possessed by DNA is first transcribed into messenger RNA (mRNA), based on which ribosomes synthesize peptides by linking together amino acids. The process in which peptides are produced from genetic information in mRNA is called “translation”, and the role of transporting amino acids to ribosomes is played by transfer RNAs (tRNAs).

Genetic information is encoded as nucleotide sequences in DNA or mRNA. In mRNA, either three out of four kinds of nucleobases, A (adenine), C (cytosine), G (guanine), and U (uracil) are arranged to form a codon, with its own meaning (T (thymine) exists instead of nucleobase U in DNA, which is replaced by U when transcribed into mRNA). The “translation” process in which ribosomes synthesizes peptides based on “codons” is broadly described as follows.

On ribosomes, “codons” in mRNA interact with a part of tRNA called “anticodons”. “Codons” so to speak function as key holes and “anticodons” as corresponding keys. At this time, ribosomes check the matching status of codons and anticodons, and accept only the matched anticodons. In that timing, peptides (proteins) are synthesized by linking together like beads amino acids delivered by tRNA (the state in which amino acids and tRNA are bonded is called “acylation”).

In sum, genetic code “codon” in mRNA corresponds one-to-one to “anticodon” in tRNA, and “anticodon” in tRNA also corresponds to amino acid on a one-to-one basis. In other words, a “codon” determines its corresponding amino acid. Genetic code is translated to peptides (proteins) in this manner. This corresponding relationship between “codon” and amino acid is called “genetic code dictionary”.

Rewriting genetic code dictionary

Figure 3

Before moving on to the explanation on Professor Suga’s original technology, another point should be mentioned. It is that a series of peptide (protein) synthesis process can be performed in a test tube with the present chemical technologies (not necessarily limited to Professor Suga’s technology).

Desired peptides (proteins) can be obtained by mixing amino acids needed for the peptide (proteins) synthesis and ribosomes, and adding to them mRNA with the genetic code of the peptides to be synthesized. This process is called “cell-free translation”.

However, the technology can go as far as producing “normal type peptides”. It is not capable of incorporating nonstandard amino acids.

What made this possible is the “flexizyme”, an artificial RNA catalyst (ribozyme) developed by Professor Suga. Flexizyme is capable of binding (acylating) any amino acids including nonstandard amino acids to tRNA. What this exactly means is so to say the hacking of program of life.

Figure 4

As mentioned earlier, ribosomes check the corresponding relationship between “codon” in mRNA and “anticodon” in tRNA. However, ribosomes are not concerned with which amino acids are acylated by tRNA. They synthesize peptides assuming that accepted tRNA carries with it an amino acid with proper corresponding relationship.

Professor Suga has set his eyes on this fact. He hypothesized that ribosomes would synthesize nonstandard peptides, without knowing so, by having tRNA acylated with nonstandard amino acids. It is flexizyme that made it possible. In other words, flexizyme deceives ribosomes thereby enabling binding of any amino acids on to the corresponding relationship between “codon” and “anticodon”.

This technology, while depending on the mechanism of organisms, widely deviates from it. It is an extremely innovative technology of rewriting the genetic code dictionary, supposed to be a base of organisms, to artificially synthesize “nonstandard peptides”.