What is click chemistry? Nobel winner Morten Meldal reveals how it revolutionised the field

This is the first time the Nobel Prize is given for making something simple

32-Morten-Meldal-with-wife-Phaedria-Marie-St-Hilaire Chemist couple: Morten Meldal with wife Phaedria Marie St Hilaire | Nirmal Jovial

Interview/ Morten MeldAl, Danish scientist and Nobel laureate

Chemistry is everything, including when you fall in love.

That is Danish scientist Morten Meldal’s oft-repeated statement. His wife, Phaedria Marie St Hilaire, also a distinguished scientist, agrees. Dominican-born Hilaire, founder of the nonprofit The Professional Women of Colour (ProWoc) network, says that “the chemistry of love” between them ‘clicked’ during their shared lab endeavours.

Meldal, along with American chemists K. Barry Sharpless and Carolyn R. Bertozzi, won the Nobel Prize in 2022 for their groundbreaking discovery of 'click chemistry,' a revolutionary method for constructing complex molecules. This innovation holds immense potential to shape our future. But in an exclusive chat with THE WEEK, Meldal, 70, remains humble, characterising it as something simple. Excerpts:

You often mention that your curiosity and early interest in science was instilled by nature, on your grandfather’s farm.

Yes, I have a lot of wonderful memories from my childhood. That’s why I love nature so much, in particular in connection with being in nature. I have very clear images of sitting on a cherry tree, eating the wild cherries and then going to the beach and swimming. I think that childhood should be a happy time where you learn all of these things and get a feeling for what the world is all about.

Your Nobel Prize was for click chemistry. Building complicated molecules is something very important in different domains. Your discovery introduced an efficient and time-saving method to create these complex molecules. What is click chemistry and how has it revolutionised the field?

I always use the comparison with Lego, the building blocks that originated in Denmark. You can put Lego blocks together and construct new architectures from them. In the same way, we can take a block, say a functional protein or carbohydrate, which is like a signalling molecule, and put that on the protein with a click reaction. So, we click them together, like snap, snap, snap, and we don't need to use any of the normal chemistry to do that. We just use click reaction again and again in this process, and we get very complex architectures with multiple functions. So, we make small molecular robots out of building blocks. The thing is that it could not be done before. So, it is an entirely new field that you open up with this click reaction. It is a new type of chemistry, which is completely perpendicular to all other chemistries. So, it doesn't influence the other chemistries, and the other chemistries don't influence this chemistry. So, we can do these normal chemistries first and then we can click things together to make very complicated architectures without any kind of conventional chemistry around it.

In 2002, Sharpless and you independently came up with the ‘copper catalysed azide-alkyne cycloaddition’, which is now regarded as the crown jewel of click chemistry, and won the Nobel in 2022. Did you expect it?

No. We did not have any idea. In 2006, we could see that the number of citations was increasing exponentially. So, something happened. Of course, biologists got hold of it, material scientists got hold of it and so on. And in 2013, Chemistry and Engineering News was talking about click chemistry as Nobel Prize-worthy. But then nothing happened.

This is the first time the Nobel Prize is given for making something simple. Normally, it is the opposite; [you are awarded when] you make something complicated.

Could you please share how some of the most significant applications of click chemistry emerged over the last two decades?

In Halle, there is work going on to develop aeroplane paints, which are self-healing. So, if you get a crack in the paint, instead of getting corrosion in the wing, it should glue together again and click. So, you get a new polymer instead of corrosion. The other thing is in materials―a lot of coatings are clicked today. You also have [newer] strong materials [created using click reactions]. You have drugs, which are now today synthesised almost exclusively in water, instead of all these organic solvents that you have to recycle and distil. You can now do these kinds of complicated reactions in water due to the selectivity of the click reaction. So, you don't need a lot of extra things around your molecule to make the reaction work. Well, it is already in use in the development of two compounds [to treat] liver fibrosis and lung fibrosis. We have two compounds that are in the clinical trial stage, and these are made exclusively in water by clicking together relatively complex carbohydrates and aromatic compounds.

How is this being used in cancer treatment?

Two groups are working on cancer treatments at the moment. One is using the click reaction to attach a radioactive atom to a ligand (an ion or molecule attached to another) that searches out the cancer cell and kills it. So, by searching out the cancer cell, and then sitting on the cancer cell, it can deliver the radioactivity where it wants it and kill the cell. The other one is not our click chemistry, but the TCO chemistry, where you can first attach one component on a cell, and then you have the component sticking out. Then you come with the other component and that component will react. And, in the process, it releases a cytotoxic compound that kills the cell. So, when it clicks, it kills and it can only click on the cells that are sick.

What are the applications of click chemistry in Alzheimer's treatment?

In the development of Alzheimer's treatment methods, we are using click chemistry to hold on to molecules, to maintain the structure of molecules that shall recognise the Alzheimer's plaque and dissolve them.

A lot of DNA research areas are also being explored by employing click chemistry.

Yes, DNA can be conjugated, so we can click together two molecules―a protein and a DNA or two pieces of DNA, or RNA and DNA―you can mix any way you like.