Three natural compounds that prevent coronavirus from replicating identified

The Unit for Drug Discovery laboratory of the Institute of Biomedical Sciences of the University of São Paulo (ICB-USP), in partnership with researchers from the University of Hamburg and the Deutsches Elektronen-Synchrotron (DESY), both from Germany, identified three possible compounds for the treatment of Covid-19.

These are natural compounds selected in a screening of 500 drugs, which have shown promise in inhibiting the PLpro protein — one of the enzymes responsible for the proliferation of Sars-CoV-2. All three compounds, 4-(2-hydroxyethyl)phenol (YRL), 4-hydroxybenzaldehyde (HBA) and methyl 3,4-dihydroxybenzoate (HE9) are phenol derivatives and classified as polyphenols, a class of bioactive compounds present in plants. .

Published in the journal Communications Biology, the research showed that the compounds inhibit between 50% and 70% the action of this enzyme. The tests were performed on Vero cells (a lineage derived from monkey kidney) and compared with a group of cells that did not receive the compounds. The Vero lineage has similarities with the human cell and is widely used as an experimental model in this type of study.

“When we inserted the compounds into infected cells, we found that they prevented the replication of the coronavirus by reaching PLpro, which has the ability to inactivate immune system cells, which can lead to severe cases of the disease. replicate, the infectious viral particles were eliminated”, explains Edmarcia Elisa de Souza, post-doctoral student at ICB-USP.

“It is worth mentioning that the compounds did not show toxicity. In other words, there was no damage to the integrity of the cells, especially at low concentrations in which the compounds showed antiviral activity”, he adds.

New therapeutic target

The discovery of this therapeutic target is very relevant, because it is an alternative to what has been done in science. “There is little in the literature about PLpro, so any new knowledge about it is important. Knowing that it is possible to inhibit the replication of Sars-CoV-2 through this protein is a great discovery, as most studies for treatments of Covid -19 targets Spike and 3CL proteins. We were able to show that there are more options if these studies do not advance”, reinforces Souza, who has a postdoctoral fellowship from Fapesp.

The next step is to carry out tests in animal models to better assess the effectiveness of the three compounds. If successful, it will be possible to move on to clinical trials. “The compounds were isolated from nature, there is no record of their use except in primary research, and the verified efficacy opens the possibility for new therapies,” he says.

The leader of the research in Brazil is Professor Carsten Wrenger, who receives support from Fapesp for the project Structural dissection of assisted nanoparticles and drug delivery in human infectious diseases.

Compound selection

In total, six compounds selected by the team of researchers from Germany were evaluated. “Our collaborators observed the degree of interaction between the compounds and PLpro. This was done by means of X-ray crystallography, an innovative method that is still not very widespread”, informs Souza.

Crystallography allows fusing the compound to the protein and observing whether small crystals were produced in this union. These crystals could not be seen in the light of traditional microscopes. “By analyzing the crystals, we were able to produce three-dimensional models of the structures to identify whether they bind and where this happens. The more connection points between them, the greater the affinity”, explains Professor Christian Betzel, leader of the study at the University of Hamburg (Germany). ) and visiting professor at ICB-USP.

The effectiveness of the three compounds against Sars-CoV-2 was later analyzed in infected Vero cells at the BSL3 Cell Culture Facility for Vector and Animal Research, of the Department of Parasitology at ICB-USP. It is a biosafety level 3 (NB3) laboratory, which provides protection to researchers who work with the cultivation of pathogenic microorganisms.

The article “Antiviral activity of natural phenolic compounds in complex at an allosteric site of Sars-CoV-2 papain-like protease” (“Antiviral activity of natural phenolic compounds in complex at an allosteric site of the Sars-CoV-2 papain-like protease” “) can be read here.

^{With information from the ICB-USP Communications Office}