On October 5, the Royal Swedish Academy of Sciences announced that the 2022 Nobel Prize in Chemistry will be awarded to Caroline Bertozzi of Stanford University in the United States, Morton Merdahl of the University of Copenhagen in Denmark, and Scripps in La Jolla, California, USA. Carl Sharpless of the Research Center for their contributions to the development of click chemistry and bioorthogonal chemistry.
This year’s Nobel Prize winners in chemistry are all from the field of new concept chemistry, and the award involves two new concepts, namely click chemistry and bioorthogonal chemistry. Click chemistry, also known as link chemistry and speed-dating chemistry, is a concept proposed by Sharpless in 2001, which refers to the rapid and reliable chemical synthesis of various molecules through the splicing of small units. In 2003, Bertozzi first proposed the concept of “bioorthogonal chemistry”, which refers to chemical reactions that occur in biological systems without interfering with endogenous biochemical processes.
According to the Royal Swedish Academy of Sciences, Sharpless and Merdaer laid the foundation for click chemistry; Bertozzi, who proposed bioorthogonal chemistry, raised click chemistry to a new dimension and has begun to use related technologies in living organisms.
The origin of click chemistry
Organisms in nature generate kaleidoscopic substances in a variety of natural ways, which is where the inspiration for click chemistry comes from. Researchers have observed that with only more than 20 kinds of amino acids and more than 10 kinds of primary metabolites, organisms can splice tens of millions of very complex biomolecules synthesized from amino acids and monosaccharides, such as proteins and polysaccharides. At the same time, this kind of chemical splicing has a clear tendency, mainly through the formation of carbon-heteroatom bonds (CXC) to complete complex splicing.
Sharpless’s explanation of click chemistry is that instead of investing a lot of manpower and material resources to synthesize 0.1 mg of complex natural products, it is better to spend resources on developing efficient synthesis methods. Instead of spending a lot of effort synthesizing carbon-carbon bonds, chemists should spend more effort building carbon-heteroatom bonds. However, not all carbon-heteroatom bonds are worth studying, and attention should be paid to the synthesis of chemical bonds that release high free energy, which is the focus of click chemistry research.
The core idea of click chemistry is to quickly and reliably complete the chemical synthesis of various molecules through the simple splicing of small units guided by molecular functions. This chemical reaction occurs rapidly at room temperature and produces no by-products.
two time nobel laureate carl sharpless
Obviously, the idea of click chemistry is “cutting out the complex and keeping it simple”, which is of great significance to researchers in the field of chemistry. In many frontier fields of chemical research, researchers are often troubled by increasingly complex molecules of matter. In the process of drug development, researchers often involve artificial reconstruction of natural molecules with medicinal properties. Studying and synthesizing these molecular structures is complex and time-consuming, and the production cost is extremely high. Click chemistry can simplify complex molecules and even directly construct functional molecules.
In 1996, Professor Gaida of the Department of Chemistry at the University of South Florida in the United States found through computer simulations that there may be as many as 1063 molecules that can be used as drugs, but only if the molecules contain less than 30 non-hydrogen atoms and the relative molecular weight is less than 500. Composed of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, and bromine atoms, it is stable at room temperature and in oxygen and water. However, the number of chemical molecules currently used in drug discovery is far less than this number. Therefore, a series of reliable and highly effective drugs can be developed more quickly and simply by imitating the mode of click chemistry in nature.
In order to achieve the goal of reducing complexity, the ideal click chemistry has some characteristics, such as simple reaction conditions, easy access to raw materials and reagents, rapid synthesis reaction; it can occur at room temperature, and the yield is high; by-products are harmless or have no by-products ; Do not use a solvent or react in a benign solvent, the solvent is preferably water; the product is not sensitive to oxygen and water, etc.
The fruits of click chemistry
Under the guidance of the basic theory of click chemistry, Sharpless and Merdahl independently completed the work known as the “crown jewel” of click chemistry – the copper-catalyzed azide-alkyne cycloaddition reaction. It is a chemical reaction that is both simple and efficient, with high yields and a wide range of applications, and is now widely used in drug discovery, mapping DNA molecules and creating new materials.
HIV is divided into two categories, HIV-1 and HIV-2, but HIV-1 is the main cause of disease, and inhibiting HIV-1 is the main mechanism of current AIDS drugs. Although a variety of inhibitors have been approved for use since 1995, and a large number of inhibitors are undergoing clinical trials, the mutation of the virus has caused the effect of the drug to be unstable. In addition, resistance to HIV-1 inhibitors is growing at a worrying rate.
In 2006, based on the click chemical reaction, the Sharpless team developed HIV-1 protease inhibitors, which can inhibit the replication of various variants of HIV-1. The success of HIV-1 protease inhibitors has both the basis of click chemistry and the help of multidisciplinary knowledge. Although protease inhibitors are the second-line therapy for most AIDS patients in the world, with such drugs, it can play a “background” role for HIV-infected and AIDS patients.
In addition, in the field of protein research, click chemistry has also achieved certain results. In 2009, the Sharpless team discovered an antibody-like protein capture agent based on click chemistry, which provides convenient conditions for the detection and utilization of proteins. In the past, researchers relied on antibody-based capture reagents to detect proteins, and such antibodies should show a high degree of correlation and selectivity to their homologous proteins. However, antibodies are very expensive and unstable, easily affected by temperature, humidity, and pH. The Sharpless team used click chemistry as a screening method to construct a multi-ligand protein capture reagent, and found that this capture reagent is simpler and more effective than antibody capture reagents. This method not only helps to find useful protein molecules, but also detects some microorganisms, such as viruses.
New heights in bioorthogonal chemistry
Bioorthogonal chemistry is a set of chemical reactions that use non-natural functional groups (functional groups are atoms or atomic groups that determine the chemical properties of organic compounds) to explore and understand the physiological and biochemical processes in organisms, that is, clicks that work in organisms chemical reaction. From this perspective, Bertozzi has raised click chemistry to a new level.