Recently, the 2022 Nobel Prize in Chemistry was awarded "Click Chemistry and Bioorthogonal Chemistry", which is also the second time K. Barry Sharpless won the award.
Bioorthogonal chemistry? em, this is a very strange name. Today I will talk about my personal understanding. In fact, all scientific research is to better serve human beings, and this time, bioorthogonal chemistry is no exception. Its purpose is to track the fine changes in life and serve precise drugs better.
1, tracking the fine changes in life
Accuracy is a very important word. To give a common example, today's medicines basically cannot achieve the accuracy of "treat headaches to treat head and feet to treat feet", and often spread throughout the body. Whether it is headache, toothache or local inflammation, usually taking medicine is taken orally or injected. Oral administration is followed by the esophagus to digest and absorb the gastrointestinal system and then runs with the blood. The injection reaches the muscles and then runs with the blood. Many times you probably feel it is wasted.
precision is a pursuit.
The same is true for cells. Cells are actually very complicated. It is estimated that tens of thousands or even hundreds of thousands of molecules exist, including protein , nucleic acids, sugars, etc. If you throw some medicine in, who is it having sex with, and you look confused.
So this gave birth to the famous tracer method, which is to track the activity process of a certain component.
However, this is not easy.
2, tracer method
The first generation tracer method is called isotope labeling, which can track total proteins and nucleic acids.
We have studied high school biology . A. Hershey and M.Chase used E. coli T2 phage as material, labeling the shell and DNA of the phage with different radioisotopes , respectively. The DNA is a real genetic material by isotope tracer method.
However, this method has some shortcomings.
First of all, this requires a high level of laboratories and requires special equipment.
Secondly, isotope , there is radiation risk
Third, and most important point, the substances it tracks are very grand classification , such as proteins and DNA, but the human body has many proteins, such as a cell, there may be thousands of protein . If we need to stare at a specific protein, we are sorry, we can't do it. One of the second generation tracer methods: fluorescent protein labeling, tracking protein
At this time, someone proposed whether it can be labeled for a certain protein alone. This is the research content of the Nobel Prize in Chemistry in 2008, fluorescent protein. By encoding a certain colored protein through a gene, and then connecting this gene with the gene we need to study, the protein we study can fluoresce. There are many fluorescent proteins currently available, as shown in the figure below.
This method is basically the most mainstream method in life sciences. I guess you can see traces of fluorescent proteins when reading various articles.
However, there is one problem with this method, that is, fluorescent proteins are gene-encoded, and they are actually large molecules, which may cause structural changes in the protein you are concerned about. Then, whether this structurally changed protein will have an impact on the experiment is a question worthy of attention.
The second generation tracer method: single-molecular fluorescence imaging
SMD (Single Molecule Fluorescence Detection). Just look at this name and tracking single-molecule is also in line with our needs.By measuring the spectral properties of a single molecule, real-time monitoring of the chemical reaction pathways
This is very good, but I have already won the Nobel Prize for . At that time, someone had discussed why Zhuang Xiaowei , who is doing this direction, did not win the Nobel Prize.
3, the content of this Nobel Prize - Bioorthogonal Chemistry
Personally, I think that this Nobel Prize is also one of the second generation tracer technology. However, the advantage of this technology is that the tracer is smaller.
as shown below, then a small group is much smaller than fluorescent protein (in hundreds or thousands of ratios).
Then this group can be traced.
This experiment further reduced the impact of tracking, which is to see it and minimize interference to the entire cell as much as possible.
Originally this was used for tracking sugars and has been used in a variety of macromolecules.
4, not just tracer
Since tracer is implemented by adding a certain group to a certain molecule, then this means that this is a switch, which is the exquisiteness of the word click. Since it is a switch, it means that this can directly affect the molecules, so it can not only be used for tracking, but also directly contact and react. This is the premise of precise drugs.
We can imagine that our drug has arrived somewhere, but it is just there, and then we add a small molecule component according to the needs, and then click it, and the two are combined, so we start the reaction, and choose like a time bomb.
This is the new purpose of this switch, just like the figure below
Of course, this is theoretically a development of ideas and perspectives. The specific one depends on the optimization of the application process.
