For pharma chemists, why it is important to teach molecules to take a ‘left’ turn

Often, the molecular ‘lefties’ perform useful biochemical functions in our bodies. At the same time, their mirror-image ‘righties’ may be less effective or, in some cases, cause undesirable side effects. This is why chemists seek ways to produce only the desired form when manufacturing medicines.

The 2026 Nobel Prize in Chemistry has been awarded to French chemist Henri B Kagan and Japanese chemist Kenso Soai for their discoveries regarding how to produce molecules with a preferred handedness. The award ceremony will be held in Stockholm, Sweden, on December 10.

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In school science textbooks, molecules are often illustrated using ball-and-stick models, with atoms represented as balls together with the bonds connecting them as sticks. Let us use this familiar ball-and-stick model to imagine a molecule called propylene oxide. In a simplified drawing, its structure can resemble a little dog, with a triangular body and projections that look rather like a head and a tail.

Now place this molecule next to a mirror. The head-like and tail-like projections would appear on opposite sides. Both structures contain the same kinds of atoms, connected by the same chemical bonds; what differs is their three-dimensional arrangement. The two structures are mirror images of each other. Yet, no amount of turning or rotating one will make it fit perfectly over the other.

Think of your left-hand and right-hand gloves. They look alike, but no matter how you turn them, you cannot make one fit perfectly over the other. We cannot wear a right-hand glove comfortably on the left hand.

Certain molecules display precisely this property. It is called chirality. The two mirror-image forms are known as enantiomers. As in propylene oxide, the two configurations of such molecules are designated R, often identified as right-handed, and S, left-handed.

Almost all the physical and chemical properties of such mirror-image molecules are almost identical. But their biological activities differ. In particular, they may behave differently when interacting with other biomolecules that themselves have a particular handedness.

A chemist can use a catalyst with a particular chiral configuration to guide a chemical reaction so that one molecular form is produced in greater quantities than its mirror image. Hery B Kagan’s research helped establish the principles underlying such selective chemical reactions. Image: nobelprize.org

Thus handedness matters. For example, our bodies cannot metabolise L-glucose the same way they metabolise D-glucose. If L-glucose were to replace D-glucose as our principal source of sugar, our bodies would not be able to obtain energy from it in the usual way.

It also influences the effectiveness, or otherwise, of medicines.

Many of us take omeprazole to relieve heartburn and related problems caused when stomach acid flows back into the oesophagus, a condition known as gastro-oesophageal reflux disease (GERD). Omeprazole also exists in two mirror-image forms of molecules, designated R and S. While the S form is potent and effective, the R form is slow but does not cause any harm.

When omeprazole was introduced in 1988, it was a mixture of the two forms. Later, esomeprazole, which contains only the S form, was developed and found to have certain advantages in how the body processes the medicine. Neither form harms the body, and consuming the mixture is not harmful.

On the other hand, bupivacaine, a local anaesthetic used to numb parts of the body during surgery, is different. Like other biomolecules, this also exists in R and S forms. The R form has more side effects and may harm the heart. The S form has a relatively safer profile. This led to the development of levobupivacaine, a medicine containing the S form alone, which is now used in clinical practice. Thus, there is a case for developing exclusively left-handed molecules for medicine.

Let us return to cars and their steering wheels. In India, the steering wheel is generally on the right because we drive on the left side of the road. In the United States, the opposite convention applies: vehicles travel on the right, and the steering wheel is generally on the left. Car manufacturers produce vehicles to suit the driving rules of the countries where they will be used.

Living organisms, too, in like manner produce biochemical molecules with particular configurations. Take vitamin C, for instance. Ascorbic acid in fruits such as lemons has the L configuration. Plants synthesise L-ascorbic acid through specific biochemical pathways. Citrus fruits hardly ever produce the D configuration, which the plant (and the animals that eat the fruits) cannot metabolise.

The preference for left-handed molecules is not confined to the biochemical world. Remarkable asymmetries appear even among the fundamental particles of nature. In weak interactions, neutrinos (electrically neutral, very light subatomic particles) are observed with left-handed helicity (the projection of a particle’s spin on its momentum). Quarks (another subatomic particle) also exhibit a preference for left-handedness. More intriguingly, some studies show that the spiral arms of galaxies swirl towards the left. From the molecules of life to the largest structures in the Universe, these questions prompt us to wonder: why does nature favour one handedness in some circumstances?

We still have no complete answer. Scientists continue to investigate why life came to rely on particular molecular configurations and why certain fundamental interactions distinguish between left and right.

Let us go back to car manufacturing once again. The Volkswagen factory at Kariega in South Africa makes cars mostly for export, very little for the domestic market. Depending on the destination, it produces vehicles with either right-hand or left-hand steering. In much the same way, when certain chiral molecules are synthesised using ordinary chemical methods, the result is often a mixture containing nearly equal amounts of the two mirror-image forms. Of these, the right-handed molecules are often weak, less effective or at times even dangerous.

This brings us to a practical challenge. When producing medicines and other useful substances, how can we make only the molecular form that we want, rather than a mixture of both? This was one of the problems confronting pharmaceutical chemists.

Kenso Soai discovered, the product molecule can act as a catalyst, helping more molecules of the same kind form. In a sense, this is like removing a thorn with another thorn. A molecule with a particular handedness encourages the formation of more molecules with that same handedness. This phenomenon is known as autocatalysis. Image: nobelprize.org

Henri Kagan made an important contribution towards solving this problem. To understand the basic idea, imagine an assembly line in a car factory. Suppose the robot that fits the steering wheel is designed to install it on the left side of the car. Fitting the wheel on that side would be easier and faster than fitting it on the right. As a result, more cars with left-hand steering would roll off the assembly line.

Similarly, a chemist can use a catalyst with a particular chiral configuration to guide a chemical reaction so that one molecular form is produced in greater quantities than its mirror image. Kagan’s research helped establish the principles underlying such selective chemical reactions.

Building on Kagan’s work, researchers at AstraZeneca developed a modified method to produce esomeprazole, the S form of omeprazole. This medicine has been in use since 2000.

Kenso Soai took the idea a step further. In the chemical reaction he discovered, the product molecule can act as a catalyst, helping more molecules of the same kind form. In a sense, this is like removing a thorn with another thorn. A molecule with a particular handedness encourages the formation of more molecules with that same handedness. This phenomenon is known as autocatalysis. This is akin to a chemical snowball effect.

In such an autocatalytic reaction, even a small initial excess of the preferred molecular form can be enough to set the process in motion. The molecules already present promote the formation of more molecules with the same handedness. As the reaction proceeds, the small initial imbalance can grow larger and larger. In a study published in 1995, Soai and his colleagues demonstrated how this process could amplify an initial imbalance in molecular handedness, yielding a mixture overwhelmingly dominated by the preferred form.

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Kagan and Soai’s discoveries open up fascinating opportunities for the future. It may provide new ways of selecting and producing biochemical molecules with the desired handedness. Since molecular handedness can influence how substances behave in the body, these findings could eventually help researchers develop medicines with fewer side effects and contribute to precision medicine, in which treatments are chosen to suit the needs of individual patients.

The potential is manifold. When chemical reactions produce both mirror-image forms of a molecule, separating the desired form can add time, cost and waste. Asymmetric synthesis allows chemists to favour one form from the outset, helping manufacture many medicines more efficiently. Controlling molecular handedness can also create polymers, liquid crystals and optical materials with specialised properties. In some pesticides, selecting the more active form may reduce the amount needed, potentially lessening chemical waste and environmental impact.