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This main protease would be "like the digestive system, the one that transforms the polyproteins into the virus," according to scientist Ernesto Estrada, from the Aragonese Agency for Research and Development Foundation.
The virus that causes covid-19 could have an Achilles heel inside: an enzyme essential for its survival and about which new details are now known, which can be used for the development of drugs, according to a study published this Tuesday 'Chaos' magazine.
The scientist Ernesto Estrada, from the Aragonese Agency for Research and Development Foundation (Araid) who works at the University Institute of Mathematics and Applications of the University of Zaragoza, signs this study focused on the main protease of the coronavirus.
This main protease would be "like the digestive system, the one that transforms the polyproteins into the virus," he explains.
Estrada has discovered a significant increase in the sensitivity of the main protease of SARS-Cov-2 against small alterations that can change its structure, compared to that of the SARS-CoV-1 coronavirus, which appeared between 2002 and 2003.
The scientist studied how this increased sensitivity could be used so that protease inhibitors (organic molecules, drugs or new chemical compounds) could attack it, since without it the virus cannot survive.
The results of the study open the door to using massive molecular screening protocols to identify potent inhibitors of the main protease of SARS-CoV-2 and, consequently, for the development of new drugs.
The main protease in coronaviruses does not usually change as much as the Spike (S) protein can, which is what these viruses use to enter human cells. "That's one of the advantages of attacking it," Estrada says. The other is that there is no such protease in humans, so the specificity of the drugs can be very significant.
Estrada closely analyzed the main protease of SARS-Cov-2, which allowed him to discover differences with that of SARS-Cov-1, despite the fact that both have 96% similarity in their amino acid sequences.
Using standard mathematical techniques, these subtle differences are imperceptible, so he had to use more advanced techniques developed by him and his team a couple of years ago.
The researcher has experience in the mathematical analysis of networks, which is why he has decided to treat this enzyme as if it were a network and, to do so, he has represented its structure in a mathematical way, in which each of its 303 amino acids is a node and the physical interaction between them is represented with edges.
A kind of "spider web" is thus drawn that represents the main protease of the coronavirus.
When an insect falls into a spider web, a disturbance is generated in the tissue that alerts the arachnid to the location of the prey. A spider web would be more effective the more sensitive it is to transmit those disturbances and the farther they are transmitted.
If we compare the "spider web" of the 2003 coronavirus with that of the current one, we see that the latter is almost 2.000% more susceptible to the transmission of these disturbances, which can be produced by any molecular interaction in the intracellular environment.
Furthermore, the SARS CoV-2 protease is capable of transmitting these perturbations much further than the CoV-1 protease does through the protein.
Continuing with the simile of the spider web, Estrada indicates that the prey that fall into it would be the analogue of the inhibitors, which are always deposited in a very specific "place", a small group of amino acids, that surround the active site of the spider. protease with which the enzyme performs its function.
Estrada studied three types of inhibitors, two of them "extremely powerful", and discovered that to the extent that an inhibitor "is capable of reducing this sensitivity to the transmission of perturbations as little as possible, the more effective it will be against the protease."
This greater sensitivity to perturbations makes the protease more effective in its work as an enzyme, but, at the same time, it leaves an open door that "can be an Achilles' heel" in favor of inhibitors.
