|Photo: Karoli Arvai / AFP|
In the largest study ever conducted on the weaknesses of Sars-CoV-2, a group of 200 scientists in six countries discovered survival mechanisms for this and the other two potentially lethal coronaviruses – Sars-CoV-1 and Mers-CoV – that can be target of treatments. The work, developed in 14 research institutions, was published in the journal Science and presented yesterday, in an online press conference. According to the authors, there are already drugs capable of attacking these vulnerabilities.
Before covid-19, there were two coronavirus epidemics: severe acute respiratory syndrome (SARS), in 2002/2003, and Middle Eastern respiratory syndrome (Mers), in 2012. The study identified molecular mechanisms crucial for the survival of pathogens, which are the same in all three, suggesting that drugs whose target is these means of action of the viruses could fight other microorganisms of the same family that appear in the future.
To discover the Achilles heel of the coronaviruses, the researchers looked at a bank of medical records containing information from 740,000 patients with Sars-CoV-2. Previously, the same group published preliminary data in the journals Nature and Cell. Now, they have done the complete analysis of the set, using biochemical, proteomic, genetic, structural, bioinformatics, virological and imaging approaches. The goal was to identify the target proteins and cellular processes that allow coronaviruses to interact with the host and successfully infect it.
Taking advantage of the mapping of how viral proteins interact with those of the target host cell, called interactome, the team compared the data from Sars-CoV-2 to that of previous coronaviruses, highlighting several important cellular processes that are shared between the three. These common pathways and protein targets represent high priority targets for therapeutic interventions for this and future pandemics.
“We have been working diligently since the early days of the identification of Sars-CoV-2 by asking ourselves about the biology and functional activities of these viruses, and looking to exploit their weaknesses,” said Veronica Rezelj, virologist at the Pasteur Institute in Paris. “In our most recent study, we increased our knowledge base by directing research to two additional coronaviruses, elucidating mechanisms among viruses that allow for potential therapeutic interventions.”
Christopher Basler, professor and director of the Center for Microbial Pathogeny at the Institute for Biomedical Sciences, in the United States, says that the group’s previous work identified more than 300 host cell proteins that can interact with those of Sars-CoV-2. In the current study, Basler’s laboratory examined each for its ability to alter the growth of the virus. “The efforts have identified at least 20 genes from the host whose protein products significantly alter the amount of virus produced by infected cells,” he says. “These proteins represent potential targets for therapeutic intervention. For example, if a cellular protein is necessary for the efficient growth of the virus, a drug that inhibits the cellular protein must delay infection, ”he exemplifies.
The researchers also performed analyzes of clinical data on the evolution of the disease in patients with covid-19. To do this, they identified molecules in human cells that could be the target of drugs approved by the FDA, the US drug regulatory agency, and looked for the effect of these drugs on the 740,000 individuals whose medical records were made available.
The analyzes revealed, for example, that in patients treated with a non-steroidal anti-inflammatory substance called indomethacin, which targets the PGES-2 gene, the risk of disease progression was lower compared to those treated with celecoxib, drug of the same class and indication, but that does not focus on that protein. Among the people who were hospitalized, the group compared the effectiveness of the antipsychotic haloperidol, which has activity against the sigma 1 receptor, with atypical antipsychotics, which do not target that target. Half of the patients who used haloperidol progressed to the point of requiring mechanical ventilation. This indicated that typical antipsychotics (the oldest, from the 1950s, and still in use) can have significant adverse effects. Not only them, according to the researchers, but other drugs that also act on the sigma 1 receptor.
“These are powerful examples of how knowledge at the molecular level can quickly generate clinical hypotheses and help to prioritize candidates for prospective clinical studies or for future drug development. A careful analysis of the benefits and relative risks of these therapies should be performed before considering prospective studies or interventions, ”said Nevan Krogan, director of the Institute of Quantitative Biosciences at the University of California, San Francisco, and leader of the study.
“The analyzes demonstrate how biological and molecular information are translated into real-world implications for the treatment of covid-19 and other viral diseases”, agreed Pedro Beltrão, from the European Institute of Bioinformatics. “After more than a century of relatively harmless coronaviruses, in the past 20 years, we have had three mortals. By investigating the three species, we are able to predict coronavirus therapy that could be effective in treating the current pandemic and future coronavirus. ”
Strain in pigs
A study published in the journal Pnas stated that a strain of coronavirus that strikes pigs, SADS-CoV, has the potential to spread to humans. The microorganism has been circulating in China since 2016, causing diarrhea and vomiting in animals. Now researchers at the University of North Carolina say it can infect and replicate in the human airways, liver and intestinal cells. The study was done in cells, in vitro. For this reason, the authors emphasize that they are not claiming that SADS-CoV will necessarily pass to humans. “It is impossible to predict whether it could emerge and infect human populations,” they told the Daily Mail.