[Kim Byung-min's Science Village] Side Effect-Free COVID-19 Treatment... 'Asymmetric Organocatalyst' as the Solution

Catalysts, which do not change themselves
but help or control reactions of other substances
Elements that help convert nitrogen oxides in diesel engines
into harmless nitrogen and water
Many catalyst studies have won Nobel Prizes

Isomeric structures exist in nature
They differ left and right like a mirror image
One side of a drug is effective
while the other causes side effects
Asymmetric catalysts can produce only the active substances

Healthcare workers disinfecting at the public health center Photo by Yonhap News

Actually, what I want to talk about today is the ‘catalyst.’ What is a catalyst? In chemistry, a catalyst is a substance that facilitates or controls reactions between other substances without itself undergoing any change. Therefore, catalysts are not included in the final products. Catalysts are used not only in science but also as analogies in the humanities and social sciences, often compared to individuals who promote the emergence of certain events. A true catalyst should only provide assistance and must not benefit from the results. It is a noble role that does its best without being attached to the outcome.

In chemical reactions, products are not efficiently formed without catalysts, and if catalysts remain in the products, they are treated as impurities. The importance of catalysts is so significant that it constitutes a separate field in chemistry, and they are crucial in industries, especially in biochemistry and pharmaceuticals, where they can determine the outcome of products. The importance of catalysts is evident from the many Nobel Prizes awarded for catalyst research, and this time, the award was given for a particularly special ‘asymmetric organocatalysis.’

Since you already understand the meaning of ‘catalyst,’ you can probably guess that ‘asymmetric’ and ‘organic’ are important terms here. The distinction between organic and inorganic is somewhat confusing even for those studying chemistry, with various definitions. Generally, carbon compounds are called organic substances, and catalysts can be either inorganic or organic. Typically, catalysts must have enough electrons within their molecules because reactions ultimately occur through electron exchange. Until now, most inorganic catalysts have used metals with many electrons. The use of metal catalysts has been essential in the chemical industry, which requires fast reactions and high product yields. Thus, metal catalysts frequently appear in anecdotes about important events or discoveries in the history of chemistry.

On the other hand, organic catalysts emerged as biochemistry and pharmacology developed, transferring metabolic processes occurring in living organisms into the realm of chemistry. The enzymes we know are essentially organic catalysts. Compared to metal catalysts, these are large organic molecules. However, the field of organic catalysts does not seem very new, as humanity has already extensively studied biochemistry and molecular biology. So, is the remaining term ‘asymmetric’ the key to the Nobel Prize in Chemistry?

Actually, the term asymmetric is not very new either. We already knew that nature contains substances called isomers. Incidentally, this phenomenon was also discovered by W?hler, who synthesized urea. Isomers are compounds with the same elemental composition but different atomic connections or spatial arrangements. Depending on how atoms are arranged, their properties differ, making them appear as different substances. Let’s take glucose as an example. Starch and cellulose are composed of glucose (C6H12O6). Starch looks like thousands of glucose molecules linked in a long chain, while cellulose is tightly interwoven. Unlike starch, hard cellulose is difficult to break down. You may have seen cows or goats chewing cud all day. Herbivores with rumens regurgitate swallowed food to chew it again. Only a few organisms on Earth can break down cellulose. Bacteria are among them, and the rumen serves as a storage for such bacteria. Of course, some herbivores do not have rumens, including humans. Elephants, which are herbivores, do not have rumens. They must eat all day to consume some sugars and starch from their food. So, it is no surprise to see the enormous amount of undigested plant matter excreted by elephants. On the other hand, starch is easily digested. The reason is that the glucose units composing starch and cellulose differ in shape. The glucose molecules in these two substances have the same molecular formula but are isomers with slightly different shapes. They are distinguished as alpha (α) and beta (β). When alpha glucose molecules bond, they form the helical structure of starch, and when beta glucose molecules bond, they form the mesh structure of cellulose. One tastes sweet, and the other is indigestible. A minor difference in molecular arrangement results in completely different substances. Among these isomers, many exist as mirror-image molecules called enantiomers, and the term ‘asymmetric’ is used here. Like left and right gloves, they resemble each other but cannot be superimposed, hence the term asymmetric. Although these terms are not new, the driving force behind their combination and emergence is the challenge to understand nature.

Proteins that make up our bodies are composed of amino acids. Amino acids also have mirror-image isomers. The mysterious fact is that only one of these mirror-image isomers exists in the body. Only the L (levo)-amino acids, meaning the left-handed ones, participate in life processes. The D (dextro)-amino acids, or right-handed ones, are almost nonexistent. Humanity has not yet uncovered this natural secret. But we know that nature designed molecules in only one direction. Why is this important? Because of medicine. Treating diseases with drugs means external substances interact with life processes, and the body reacts differently depending on the mirror-image isomer of the substance. Only one direction of amino acid corresponds to the effective drug. For example, ibuprofen, a pain reliever and fever reducer, contains equal amounts of two mirror-image isomers. However, only the D-ibuprofen is effective. The other causes side effects. A representative case of side effects caused by ignorance of isomers was the thalidomide medical disaster. In the mid-20th century, the ineffective mirror-image isomer unexpectedly caused side effects, resulting in 10,000 birth defects worldwide.

Then, why not produce only the effective isomer when making drugs? Because we have not yet perfectly mimicked nature, synthesizing substances produces both isomers. Currently, both forms are made, and the effective one is painstakingly separated. Of course, this is not easy. However, asymmetric organocatalysis has opened a path to easily produce only one isomer. Unlike large enzyme catalysts, these are simple organic molecules derived from natural products, non-toxic, easy to synthesize, and economically viable for mass production.

Since the first paper was published in 2000, it has been the ‘golden age’ of the field of organocatalysis. More than two papers are published almost daily. This catalyst has been applied in pharmaceuticals. The flu treatment Tamiflu was produced using asymmetric organocatalysis to make only the effective isomer, avoiding side effects. Future COVID-19 treatments will also benefit from this catalyst. This influence and significance led to the Nobel Prize award. I have deliberately not mentioned the Nobel laureates’ names. This achievement cannot belong solely to the recipients. The true protagonists are the catalysts and all scientists researching them. They will gradually unveil nature’s secrets.

Future scientists will build on today’s researchers’ efforts and knowledge. Science is not a challenge to conquer nature but a process and system to understand it. Perhaps everyone contributing here is the true catalyst for a better world.