A pandemic focus on a notorious protein
During the COVID-19 pandemic, Gabriela Dias Noske and other researchers at the University of Sao Paulo — like scientists all over the world — shifted their research projects toward the SARS-CoV-2 virus. Dias Noske was working with proteases at the time, so she pivoted to the main protease of the virus and worked to assess its structural features for drug design.
The research was not without its challenges, especially during the pandemic, with lab resources scarce and inaccessible at times.
“It was very demanding because we were working with no weekends and no holidays, just working with only four people in the lab to keep the lab working,” Dias Noske said. “But it was a very nice thing to be able to be there and doing something for a pandemic.”
The main protease, or Mpro, of the SARS-CoV-2 virus is an important protein in disease progression. Dias Noske and colleagues sought to determine the structural basis of antivirals such as nirmatrelvir and ensitrelvir and how these drugs inhibit Mpro and its mutations.
Dias Noske conducted activity-based screening assays and structural data analysis using crystallographic data. She found many key interactions between the antivirals and the Mpro mutations, which will aid in developing the next generation of antivirals that inhibit Mpro and its mutations.
For the paper about this work published in the Journal of Biological Chemistry, Dias Noske received a 2024 JBC/Herbert Tabor Early Career Investigator Award.
A physics major during her undergraduate studies, Dias Noske decided to specialize in biomolecular physics in grad school. She began by using crystallography to solve the crystal structure of viral proteins. Having worked on several viruses during her doctoral studies, she is now working on cryo-electron tomography, imaging virus–host interactions within cells using a microscope.
Mutations and drug activity
Antivirals are used to inhibit viral replication and stop the progression of viral diseases like COVID-19. Researchers need to understand the structure and mutations of Mpro as it is a crucial part of viral replication and can cause antiviral resistance.
Gabriela Dias Noske and a team at the University of Sao Paulo studied 14 naturally occurring polymorphs of Mpro against the antivirals nirmatrelvir and ensitrelvir to understand the key interactions in protein inhibition. They showed that there were changes in potency — the amount of drug required for a desired effect. The drug–target interactions were confined to a specific binding site, where the drug binds to a number of amino acid residues in the protein sequence. Changes in the structure within the binding site affect drug interactions, and the drug loses its ability to cause a desired response.
Activity-based screening assays compared potency for the 14 mutants and wild-type Mpro for the two drugs. Nirmatrelvir showed slightly lower potency for most of the polymorphs, and ensitrelvir showed significantly lower potency with respect to the wild type. The data also suggest a distinctive binding profile for the two drugs.
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