The Nobel Prize in Chemistry 2022 was awarded to scientists Carolyn R. Bertozzi, Morten Meldal, and K. Barry Sharpless for their development of click chemistry and bioorthogonal chemistry.
These techniques have been used in a number of industries, including deliver treatments which can kill cancer cells without disrupting healthy cells and sustainably and quickly produce large quantities of polymers to build materials. A one-click chemistry-based drug is currently in the works phase 2 clinical trials. Bertozzi is a scientific advisor to the company developing the drug.
We applied for a doctorate in chemistry. candidate Heyang (Peter) Zhang of the Linen Lab at the University at Buffalo to talk about how these techniques figure into his own research and how they have transformed his field and other industries.
1. How do click chemistry and bioorthogonal chemistry work?
click chemistry, as the name suggests, is a way to build molecules like assembling Lego blocks. It takes two molecules to click, which is why researchers refer to each of them as click partners.
K. Barry Sharpless and Morten Meldal independently discovered that Azidea high-energy molecule with three nitrogens bonded together, and alkynea relatively inert and naturally rare molecule with two carbons triply bonded together, are excellent click partners in the presence of a copper catalyst. They discovered that the copper catalyst can bring the two pieces together in an optimal arrangement that fits them together. Before this technique, researchers had no way to quickly and precisely manufacture new molecules under accessible conditions, such as using water as a solvent at room temperature.
Chemical biologists quickly realized that click reactions can be a fantastic way to probe living systems like cells because they produce little or no toxic byproducts and can occur quickly. However, the copper catalyst itself is toxic to living systems.
Carolyn Bertozzi designed a workaround for this problem by remove the copper catalyst from the reaction. She did this by placing the alkyne in a ring structure, which drives the reaction forward using the ring strain produced from molecules forced into a ring shape. These bioorthogonal reactions, or reactions that occur “parallel” to the cell’s chemical environment, can occur within cells without disrupting their normal chemistry.
2. How do you use this chemistry in your work?
In a meeting, Carolyn Bertozzi said that the next steps in bioorthogonal chemistry are to find new reactions and applications for it. Our lab’s research focuses on exactly that.
My colleagues and I apply this technique to follow the molecules of interest in their natural behavior in a cell. In a living cell, we could add a probe to a receiver which plays a role in a number of cellular processes.
To find new reactions, our laboratory has spent the last 15 years pushing how fast bioorthogonal reactions can work. Speed is important because many molecules in living organisms are present in low concentrations, and using too many chemicals needed for the reaction can be toxic to the cell. The faster the reaction, the fewer undesirable side reactions.
We pioneered another way to achieve click and bioorthogonal reactions with even faster speed. Instead of using an azide and an alkyne like the Nobel laureates originally did, we used two other molecules that come together when light shines on them. With this technique, we can add molecules to the surface of a living cell in as little as 15 seconds. We can then observe how a particular structure of a cell functions in its natural environment, or detect how it changes when exposed to drugs or other substances. Researchers can then more easily test how cells react to potential treatments.
Currently, we are working to develop a new method of triggering these reactions without light. We are actively working on the use of bioorthogonal chemistry to improve PET imaging to detect and monitor tumors.
3. Why are these techniques so important to your field?
Before click and bioorthogonal chemistry, there was no way to visualize molecules in living cells in their natural state.
By analogy, imagine that you had to find a specific dollar bill with the serial number 01234567. This would be quite a daunting task. This would require you to sift through every dollar you can get your hands on and check if the serial number is the one you are looking for.
Tracking molecules in our body is just as difficult, if not more so. Because biological environments are so complex, it was previously impossible to add a probe just to the molecule of interest without accidentally labeling something else, or worse, altering the cell’s normal chemistry. With bioorthogonal reactions, however, researchers can essentially add a GPS tracker to the molecule without affecting the rest of the cell.