Ever since the birth of modern chemistry in the eighteenth century, many chemists have used nature as their role model. Life itself is the ultimate proof of nature’s supreme ability to create chemical complexity. The magnificent molecular structures found in plants, microorganisms and animals have spurred researchers to try to construct the same molecules artificially. Imitating natural molecules has often also been an important part in the development of pharmaceuticals, because many of them have been inspired by natural substances. Sometimes simple answers are the best. Carolyn R. Bertozzi, Morten Meldal and K. Barry Sharpless became Nobel laureates for founding and advancing the fields of click chemistry and bio orthogonal chemistry, which has “led to a revolution in how chemists think about linking molecules together,” the Royal Swedish Academy of Sciences said. Click chemistry enables fast and straightforward reactions, where “molecular building blocks snap together quickly,” the committee said. The principle can bring real-world benefits in the development of pharmaceuticals and medicine, including more targeted cancer treatments. Sharpless and Meldal pioneered the concept before Bertozzi “took click chemistry to a new level,” the organizers said, by developing click reactions that work inside living organisms (or bio orthogonal reactions).
Click chemistry brings two molecules together “almost like a couple of pieces of Lego,” American Chemical Society President Angela Wilson told CNN. “Bertozzi was responsible for doing click chemistry within the human body, which is absolutely remarkable,” Wilson said. “The three together have opened up new doors for us in what we can do, from pharmaceutical chemistry to materials chemistry,” and their work is already being used in manufacturing, she added. Bertozzi told reporters at the winners’ press conference over the phone that her advancements are being used “to discover new kinds of molecules we didn’t know existed,” and means scientists are “doing chemistry inside human patients to make the drugs go to the right place.”
Bertozzi, the Stanford University professor said she was told of her win in the middle of the night on the American west coast. “I can hardly breathe,” she said of her reaction. “I’m still not entirely positive it’s real.”Sharpless, a professor of chemistry at Scripps Research in La Jolla, California, meanwhile, became the fifth person ever to win two Nobels, joining a short list that includes pioneering chemists Marie Curie and Frederick Sanger. Sharpless came up with the concept for click chemistry in 2001, the same year he won his first Nobel prize for chemistry. Working independently, Sharpless and Meldal, who is based at the University of Copenhagen in Denmark, came up with what the Nobel committee described as the “brilliant reaction” synonymous with click chemistry, which involves a catalyzed reaction between azides and alkynes. “If chemists want to link two different molecules they can now, relatively easily, introduce an azide in one molecule and an alkyne in the other. They then snap the molecules together with the help of some copper ions,” the Nobel committee said in a document explaining why they had awarded the prize.”It’s used to modify materials, for instance if you want them to conduct electricity or collect light or modify surfaces to become antibacterial,” explained Johan Elf, a member of The Royal Swedish Academy of Sciences and part of the committee that decided the honor. Bertozzi developed click reactions that can be used inside living organisms – because they don’t involve copper ions which are toxic. She focused on glycan’s – complex carbohydrates that are built from various types of sugar and often sit on the surface of proteins and cells.
The Nobel Prize in Chemistry 2022 is about finding new chemical ideals and letting simplicity and functionality take precedence. Barry Sharpless, who is now being awarded his second Nobel Prize in Chemistry, was the one who started the snowball rolling. Around the turn of the century, he coined the concept of click chemistry for a functional form of chemistry, where molecular building blocks snap together quickly and efficiently. The snowball became an avalanche when Morten Meldal and Barry Sharpless – independently of each other – discovered what has become the crown jewel of click chemistry: the copper catalyzed azide-alkyne cycloaddition. Carolyn Bertozzi developed click reactions that can be used inside living organisms. Her bio orthogonal reactions – which occur without disturbing the normal chemistry of the cell – are used globally to map how cells function. Some researchers are now investigating how these reactions can be used to diagnose and treat cancer, something we will return to. Let us now follow the first of the two threads that lead to the Nobel Prize in Chemistry 2022.
Barry Sharpless believed it was time for chemists to stop imitating natural molecules. This often resulted in molecular constructions that were very difficult to master, which is an obstacle to the development of new pharmaceuticals. If a potential pharmaceutical is found in nature, small volumes of the substance can often be manufactured for in vitro testing and clinical trials. However, if industrial production is required at a later stage, a much higher level of production efficiency is necessary. Sharpless used a powerful antibiotic, meropenem, as an example. Six years of chemical development work were necessary to find a way of producing the molecule on a large scale. One stumbling block for chemists, according to Barry Sharpless, was the bonds between carbon atoms that are so vital to the chemistry of life. In principle, all biomolecules have a framework of linked carbon atoms. Life has evolved methods for creating these, but it has proven notoriously difficult for chemists. The reason is that carbon atoms from different molecules often lack a chemical drive to form bonds with each other, so they need to be artificially activated. This activation often leads to numerous unwanted side reactions and a costly loss of material. Instead of trying to wrangle reluctant carbon atoms into reacting with each other, Barry Sharpless encouraged his colleagues’ to start with smaller molecules that already had a complete carbon frame. These simple molecules could then be linked together using bridges of nitrogen atoms or oxygen atoms, which are easier to control. If chemists choose simple reactions – where there is a strong intrinsic drive for the molecules to bond together – they avoid many of the side reactions, with a minimal loss of material. Barry Sharpless called this robust method for building molecules click chemistry. Combining simple chemical building blocks makes it possible to create an almost endless variety of molecules, so he was convinced that click chemistry could generate pharmaceuticals that were as fit for purpose as those found in nature, and which could be produced on an industrial scale. Azides and alkynes react very efficiently when copper ions are added. This reaction is now used globally to link molecules together in a simple manner. A great deal of decisive scientific progress occurs when researchers least expect it, and this was the case for Morten Meldal. In the early years of this century, he was developing methods for finding potential pharmaceutical substances.
In the early 1990s, Carolyn Bertozzi began mapping a glycan that attracts immune cells to lymph nodes. The lack of efficient tools meant that it took four years to get a grip on how the glycan functioned. This challenging process made her dream of something better – and she had an idea. During a seminar, she listened to a German scientist who explained how he had succeeded in getting cells to produce an unnatural variant of sialic acid, one of the sugars that build up glycans. Bertozzi therefore started to wonder whether she could use a similar method to get cells to produce a sialic acid with a type of chemical handle. If the cells could incorporate the modified sialic acid in different glycans, she would be able to use the chemical handle to map them. She could, for example, attach a fluorescent molecule to the handle. The emitted light would then reveal where the glycans were hidden in the cell. This was the start of long and focused development work. Bertozzi started searching through the scientific literature for chemical handles and a chemical reaction she could use. This was no easy task, because the handle must not react with any other substance in the cell. It had to be insensitive to absolutely everything apart from the molecules she was going to link to the handle. She established a term for this: the reaction between the handle and the fluorescent molecule had to be bio orthogonal.
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