Originally published in Jornal da USP on March 10, 2023.
Study determined how antivirals affect the structures of the coronavirus and how variants increase resistance and negatively affect the efficacy of these drugs
A study at USP’s São Carlos Institute of Physics (IFSC) is investigating the function of viral proteases, which are fundamental structures in the life cycle of the virus that causes covid-19. The research attempts to determine how Paxlovid and ensitrelvir, antivirals developed to combat the coronavirus, affect proteases and how the circulating variants increase resistance and compromise the efficacy of these drugs. The findings are described in an article published in the Journal of Biological Chemistry.
The coronavirus is generally known as a sphere covered in proteins (“spikes”) which form a sort of envelope that contains the genetic material of the virus. “When this virus reaches a cell, after the spikes recognize the receptors, this genetic material is injected inside, hijacking the entire mechanism of the cell,” notes researcher Andre Schützer de Godoy, who leads the project. “This material produces some proteins that are essential for the survival and spread of the virus through the body, which include proteases. These proteins have become an obvious target for the development of new medications against the disease, such as the two we studied here.”
Paxlovid (nirmatrelvir/ritonavir) and Xocova (ensitrelvir) are two pharmaceuticals that were brought to market around the world last year to combat covid-19. Paxlovid was produced by Pfizer and has already been approved by the US Food and Drug Administration (FDA) and Brazil’s ANVISA, while ensitrelvir was developed by the Japanese pharmaceutical manufacturer Shionogi but has not yet received approval from the major international certification agencies; both are costly for patients. Although they are different, each focuses on the same viral target: protease.
The study focused specifically on the main active ingredient in these two medications, and the team searched the genomic databases (containing approximately 7 million genomes) for variants that exist in this protease near the active site; they found only 16. Each of these proteases was produced in the laboratory to determine how they respond when these medications are used.
“In this study we found two very interesting things. First, some of the variants that are already circulating seem to be resistant to one of these medications; in other words, they could undermine effective treatment of covid-19 by generating resistance,” notes Andre de Godoy.
“Furthermore, we observed that a single variant does not seem to be resistant to both medications. Because the two drugs are slightly different from a structural point of view, chemically speaking, these data could indicate that combining both could be a good way to avoid resistance,” he adds.
The structural characterization of these variants was conducted using X-ray crystallography in the Sirius particle accelerator at the Brazilian Synchrotron Light National Laboratory in Campinas, São Paulo. The researchers used this technique to answer questions related to the seven main variants that exhibited resistance to the medications, which made it possible to understand what provoked resistance on a molecular level.
Godoy states that this project is very important, and emphasizes the partnership with Sirius. The results were obtained approximately six months ago. In clinical terms, Godoy believes that this research opens doors to additional studies on combining these two medications (or others with the same characteristics) in order to avoid the emergence of resistant lineages.
“We will still pay close attention to these resistant protease variants, even though at this time they do not yet comprise concerns or a large-scale threat,” he adds. The study was conducted at the Brazilian Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), a Research, Innovation, and Dissemination Center (RIDC) within the São Paulo Research Foundation (FAPESP) headquartered at the IFSC and coordinated by Professor Glaucius Oliva.