For scientists, drug discovery can be a slow process. It takes time to extract natural products from plants and bacteria, screen them, and see whether they’re effective against disease. And when you finally find a winner, a new problem emerges: in nature, most of these materials occur in very small amounts.
To boost the supply chain, scientists are constantly looking for quick ways to create molecules that mimic those in nature. That’s where click chemistry comes in. Invented by 2001 Nobel Prize winner Professor K. Barry Sharpless, click chemistry has been championed as a fast, easy and cost-effective approach to molecule-making. We spoke with Professor Sharpless and his key collaborator, La Trobe University’s Professor John Moses, about the clever thinking behind this innovative brand of chemistry.
What is click chemistry?
John Moses: Click chemistry is a philosophy about how to execute chemistry. Chemistry is an instrument for creation, but the way we do it is defined by a particular set of rules. Click chemistry looks for the easy way to make bonds. We identify molecules with function, that are simple to make, and can be made in around three or four steps. There are a vast range of potential drug-like molecules out there, so why make the ones that are difficult to make? Barry has pioneered a very good set of rules that are game-changing for the discipline.
Barry Sharpless: It’s a departure from traditional chemistry. I learned the more traditional methods in a scientific culture where molecules were not impressive unless they were hard to make. It was extremely time-consuming. At any one time, you could have twenty-five scientists working on thirty different experiments, just to discover one small thing. This traditional type of chemistry is like tunnelling through Mount Everest rather than finding a sensible trail up and over – and the costs associated with working this way are significant. So I started searching for molecules that had function, could be made in three or four steps, had a guaranteed reaction and a high yield.
How does click chemistry work?
John Moses: Click chemistry relies on highly energetic ‘spring-loaded’ reactions to make molecules. Nature takes a selection of, say 20 or 30, building blocks and creates huge diversity from them. We mimic that strategy in click chemistry, but the question becomes, how do we stick the building blocks together? Click chemistry is the solution to this problem; it is the molecular mortar. What you want is a reaction that works every time, superglue basically, that ‘sticks’ everything.
There are applications for click chemistry in biology, drug discovery, chemical biology and materials. It’s probably the most useful chemistry out there.
Where did the term ‘click chemistry’ come from?
Barry Sharpless: My wife, Jan, named it click chemistry. I wanted to call it ‘neat chemistry,’ like whisky; you drink it neat. That is what we were doing, pure chemical reactions with no restraints, that were guaranteed to react. But in the United States ‘neat’ means ‘cute.’ So we decided on ‘click’ and it took off.
People often say, “Our chemistry just clicked.” It is nature’s way. You can’t talk yourself out of it and you can’t stop the reaction. Biochemists loved the methods too. They didn’t know anything about the chemistry, or the click, but they knew that it worked.
What new reactions are you working on?
John Moses: We’ve developed a new kind of reaction using sulphur fluorides called ‘sleeping beauty.’ They are silent, like sleeping beauty, until they’re awoken by a protein target or ‘prince.’ We want to use smart chemistry to re-engineer drugs, change their properties, activity and potency. Once it goes click, the bond is forever.
Barry Sharpless: Sleeping beauty is not dead, but she is not alive. She doesn’t do anything unless she finds her prince, and that is one particular protein in the human body. Once they get close, they click.
Why is bravery important to scientific discovery?
Barry Sharpless: As scientists, we all end up in places we don’t understand. When we get there, we often retreat to the places we know. It’s easier to add known things to the flask, for example, and stay where it’s safe. Throughout my career, I’ve enjoyed the thrill that comes with being scared, and the discoveries that come along with that leap into the unknown.
The opportunity to discover something new is like finding diamonds laying on the ground. By the time other people come along with their shovels and dynamite, the person who has the ability to look for something new should be somewhere else. That is what I do.
You have to come to terms with the unknown in order to find something new. Every discipline has the ability to reject what it knows and does, and discover what else might be true. There is incredible freedom in that. It is not what you miss that is important, it is what you find. It is so enriching because finding usually involves jumping into new territory. And if the first idea on that scientific journey is not absurd, there is no hope for it.
Click your clever career into place with a Bachelor of Science at La Trobe.