From the newspaper El Litoral from Santa Fe, Argentina, April 1, 2020
By Luciano Andreychuk
“Basic science is very important in all areas of human life: it is key to solving problems of all kinds”. Dr Alberto Iglesias.
Two local scientists explain why enzymes are the “Achilles’ heel” of the virus that causes Covid-19
Anyone who believes that the effective coronavirus vaccine and antiviral will appear miraculously, from one day to the next. is wrong. The production of vaccines and antiviral drugs for this pandemic will take a lot of effort and time from the world scientific community. However, basic research has already taken encouraging steps, which allow solid developments to be made in reaching an effective antiviral.
The strategy to obtain an antiviral is to produce a compound that blocks the action of a particular viral enzyme (the Mpro or 3CLpro protease) that is key to the replication of the virus once it has infected the human cell. This protease is the one in charge of “opening the Pandora’s box” from which all the evil of the viral infection is released. The protease is the weak point of the virus, and the antiviral will be a drug that could interfere with this particular enzymatic activity.
Antiviral drugs: three key steps to cut off the virus’s ability to replicate within the human body
Crystallization of molecules.
With this information, reach the “heart” of the protein and block it
The details of these processes were explained by Drs. Alberto Iglesias and Carlos Figueroa, researchers at the Laboratory of Molecular Enzymology of the Institute of Agrobiotechnology of the Littoral (IAL), a unit of double dependency CONICET-UNL. Both are biochemists and teach at the UNL Faculty of Biochemistry and Biological Sciences (FBCB).
What are enzymes? Enzymes are present in all organisms (animals, plants, and microorganisms, including viruses), and work by speeding up the chemical reactions that occur in cells. They are also proteins that participate in all biological processes. “We characterize enzymes in general, and concentrate in enzymes from bacteria, protozoa and plants. We are not engaged in studying the enzymes of this virus (Covid-19) in particular. But on March 20, a publication was published in a prestigious scientific magazine, Science, where German and Chinese scientists working on the basis of basic research studies achieved a very important objective ”Iglesias and Figueroa said.
According to Iglesias, the achievements were two:
1) crystallizing (achieving a crystalline state, which allows determining the three-dimensional structure at a very detailed level of a protein) the coronavirus protease Mpro, and
2) the construction of a small molecule targeted with high specificity to the active site of the enzyme, inhibiting its protease activity.
This international study opened a door: it is a key step to find the “Achilles heel” of the virus and developing an antiviral drug effective enough to treat this novel virus that has become a pandemic.
Drug design based on the characterization of enzyme activity is a widely used strategy in the development of many drugs for different diseases. And, in the case of Covid-19, “an antiviral with a high specificity could have been achieved. This drug was designed based on a very fine understanding of the three-dimensional structure of the enzyme, “the IAL researchers agreed.
“It is very important thing to design and build an antiviral specific enough to treat this new virus, because this virus is likely to stay with humanity for a long time” says Dr. Iglesias.
The investigation, step by step
Enzymes are proteins. Proteins are macromolecules present in living organisms, made up of smaller units that come together to form a large and complex molecule,” Iglesias explained. The crystallization of a molecule allows us to study and determine (by different techniques) its three-dimensional structure at a very precise level: “This work based on the crystallization of this virus enzyme allows us to go to a very specific site of that protein , and to know the detailed structure of the site where the enzymatic action occurs ”, added Iglesias and Figueroa. This protein is a specific type of protease, that is, an enzyme that breaks the protein chain at sites with a particular amino acid sequence.
The protease in question, which, after being crystallized, has the particularity that it “cuts” a large protein coded by the virus, and cuts it into several pieces. “By making that cut, a series of smaller proteins are generated that are derived from that large protein. Two of the proteins released after the cut are enzymes that participate in replicating the virus in the infected human organism, which has been converted temporarily into a machine that duplicated the viral genetic material.When the virus infects cells, it causes our cells to start producing it. This is the way the virus multiplies in the human body”, said the scientists.
“If this protease is blocked (by the antiviral) and is inable to cut that larger protein, there is no enzyme activity that allows for the replication of the genetic material of the virus. This is the weak point of the viral cycle, and the virus’s ability to replicate is blocked after infecting a cell, no more virus will be produced by the person infected”, Iglesias explained.
Crystallizing the protease is key to the whole process of creating an antiviral chemical: “Because this (crystallization) gives the possibility of generating highly specific inhibitors of enzyme activity. By inhibiting the action of that protease, you are preventing it from cutting the large protein and generating the enzymes that enable viral replication. In other words, the virus’s ability to replicate is cut off because the protease can’t trigger the crucial step in the replication process”, he specifies.
An effective antiviral in the horizon
After all this “detective” laboratory process – the enzymatic characterization, the crystallization of the protease, preventing the virus from reproducing in the body and blocking it -, the hope of a drug that works to treat the coronavirus appears: “That possibility of Developing an antiviral against Covid-19 exists, and (that drug) would in principle be quite specific for all coronaviruses (which is a “family” of viruses), because they all act the same way, “added the experts.
This pharmacological development would require a process of a lot of time and effort (according to international protocols, bio-ethical norms, etc.). Despite the extensive work still ahead, this work by German and Chinese scientists opens up possibilities and shows us the light at the end of the tunnel.
But they warn: “If you want to design a drug that blocks the virus and does not allow it to replicate, it will also be important to avoid that blocking the viral specific protease does not interfere with the human proteases in our body, which are important for cells they work. It helps that human proteases have different specificities, but it will be necessary to make sure that there are no collateral damage in humans ”, they concluded.
Enzyme characterization is a very useful tool not only in pharmacology and medicine, but also in other areas of biotechnology, such as bio-fuel and plant production. “That is why it is important that when research policies are established in a country, scientific development should be paramount. Science is relevant every day, but this pandemic is another opportunity for the public to take note of the relevance of science to daily life.
Furthermore, it is worth adding that, as you may have heard, the diagnosis of coronavirus is made by PCR, which is the abbreviation for Polymerase Chain Reaction. Well, polymerase is also an enzyme. In everyday life, we should become aware of the relevance of science as a tool that is always of high value to have at hand ” insisted the scientist.
Translated from the Spanish by Hannah Sivak