Research suggests new therapeutic targets for broad-spectrum antiviral drugs

Coronaviruses not only use the machinery of the human cells they infect: they modify it to achieve optimal conditions to produce viral proteins and thus spread more quickly. This is the main conclusion of a study by Pompeu Fabra University published in Nature Communications. The study identifies enzymes that modify transfer RNAs (tRNAs) –small cellular parts required to build proteins– as key elements for coronavirus infection. These enzymes are activated by the stress response of viral infection and could be a new therapeutic target for developing broad-spectrum antiviral drugs against coronaviruses. 

In the last 25 years, the world has witnessed three major outbreaks of coronavirus respiratory diseases that have been passed from animals to humans: SARS-CoV-1 in 2002, MERS in 2012, and SARS-CoV-2 in 2019. While the first two caused epidemics, SARS-CoV-2 triggered a pandemic that caused more than 7 million deaths. 

"Coronaviruses are very dangerous because of their ability to generate new variants capable of infecting humans after circulating in animal reservoirs", explains Juana Díez, director of the Molecular Virology Research Group at Pompeu Fabra University, who led the research.

At present we do not have any broad-spectrum antiviral drugs that are effective against coronaviruses. So when a new coronavirus emerges, a scenario considered highly likely among the scientific community, we will be in the same position as at the end of 2019, when we did not have the drugs to control the spread of the virus."

Juana Díez, Director, Molecular Virology Research Group, Pompeu Fabra University

Like any other virus, coronaviruses use the machinery of the cells they infect to make viral proteins and spread. In this process, tRNAs –very small cellular parts that add amino acids to the new protein based on the information they read in the RNA– are key. "Interestingly, coronaviruses need tRNAs that are in low concentrations in cells. For this reason we asked ourselves how a virus can spread so quickly within a cell where the tRNAs it needs to make its viral proteins are not abundant", outlines Elena Muscolino, first author of the study. 

Taking advantage of change

The study published in Nature Communications shows that infection causes stress that chemically alters tRNAs and changes the functioning of the cellular machinery. Thus, the cell is no longer optimized to produce its own proteins and acquires the ideal conditions to respond to stress. 

Coronaviruses have taken advantage of this situation, since "in order to manufacture stress response proteins, the same tRNAs that coronaviruses need to manufacture their viral proteins are needed", explains Mireia Puig, also an author of the work. 

This readjustment, driven by cellular enzymes that modify tRNAs, allows coronaviruses to speed up the production of their proteins without the need to generate new machinery, simply by altering the existing one. "Since changes in tRNAs are modifications of the machinery that the cell already has and not the generation of new "cell parts", viral protein production occurs rapidly and coronaviruses can spread very quickly", Muscolino points out.

The modification of tRNAs has been observed both in SARS-CoV-2, associated with serious infections, and in HCoV-OC43, which usually causes very mild cold-like signs and symptoms. Therefore, it could be a common strategy among different coronaviruses. In addition, when the activity of these modifying enzymes is blocked, viral protein production decreases significantly. 

"The tRNA-modifying enzyme is a promising candidate for developing broad-spectrum antiviral drugs capable of curbing the spread of coronaviruses", Díez states. And she adds: "A drug of this type would allow us to contain the infections caused by new coronaviruses from their initial phases and prevent their rapid expansion, and therefore, new pandemics".