Combination of drugs shows promising results against COVID-19

A study by researchers of Fiocruz and of the University of Columbia has identified promising results in a combination of antiviral drugs for the treatment of COVID-19. Scientists showed that there is a synergy between the substances, inhibiting the enzymes that allow Sars-CoV-2 to multiply more effectively. Together, the drugs may reduce viral replication about ten times more than if taken separately.

The drugs studied are already approved for the treatment of other diseases

The study, published on February 22 on Communications Biology, a Nature publication, showed that inhibitors of polymerase and of exonuclease, when combined, work together to block the ability of the virus to reproduce within infected cells.

“We studied inhibitors of an enzyme that is essential for the biology of the Sars-CoV-2, the exonuclease, which provides the virus with more genetic stability and helps it select viral variants, such as those that escape the body’s immune response, for instance. The exonuclease selects the most abundant genetic set of the virus and allows for copies of this set to be replicated, all in cooperation with another enzyme, the polymerase”, explains Thiago Moreno L. Souza, one of the coordinators of the study and researcher of the Center for Technological Development in Health (CDTS/Fiocruz).

To understand ways of fighting these mechanisms, Souza and the team developed a study of computational, enzymatic and cellular modeling that showed that a group of molecules approved to treat Hepatitis C can also inhibit the exonuclease of the new coronavirus. However, they observed that this action does not occur at a concentration ideal to fight the Sars-CoV-2. “These molecules act in a different of a thousand times of power, being much more powerful against the Hepatitis C virus”, highlights the researcher.

Researchers then turned to combining molecules that could yield more efficient results. In this case, polymerase inhibitors, such as remdesivir, approved by Anvisa and by the FDA to treat COVID-19, but still with limited clinical efficacy. “When we combine drugs that were already known inhibitors of RNA-polymerase and substances that were repositioned to block exonuclease, we obtained promising results that deserve more profound clinical research”, says Souza.

Virus mechanisms

As it multiplies the viral genome, the RNA polymerase may introduce errors that would make the new virus less efficient in its replication process. Exonuclease “reviews” the genetic sequence of the virus. From among the main RNA viruses that have medical relevance, coronavirus are the only ones with exonuclease. Its activity is necessary to reduce the number of mutations and therefore maintain the integrity and the function of its RNA genomes.

The study successfully inhibited the viral functions of replication and of revision of replication, resulting in more success in the fight against the virus. Now researchers are investigating whether their discoveries can be demonstrated in an animal model. If they can, the study can move on to the clinical trial stage, as the drugs under study are approved to treat other infections.

The study was carried out and coordinated by researchers of Columbia Chemical Engineering and by the Center for Technological Development in Health (CDTS/Fiocruz). Also involved in the research were the Oswaldo Cruz Institute (IOC/Fiocruz), the Memorial Sloan Kettering Cancer Center, and the Rockefeller University.