IMAGE: Lead author Michael Sacco (seated), doctoral student at the USF Health Department of Molecular Medicine, with the study’s principal co-investigator, Yu Chen, PhD, in Dr. Chen’s lab at the university … view More
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Photo credit: Photo courtesy of USF Health / University of South Florida
TAMPA, Florida (November 6, 2020) – SARS-CoV-2, the respiratory virus that causes COVID-19, attacks the body in multiple passages. Getting into cells deep in the lungs and hijacking the human host cell’s mechanism to make copies of itself are two of the first steps, both of which are essential for a viral infection.
New study provides insight into antiviral drug design for COVID-19 demonstrating that some existing compounds can inhibit both major proteases (M)professional), a key viral protein required for SARS-CoV-2 replication in human cells, and the lysosomal protease Cathepsin L, a human protein essential for virus entry into host cells. The study, led by researchers from the Morsani College of Medicine (USF Health) of the University of South Florida Health and the University of Arizona College of Pharmacy, was published today Advances in science.
“If we can develop compounds to stop or significantly reduce both processes – virus entry and virus replication – such double inhibition can improve the effectiveness of these compounds in treating coronavirus infection,” said Yu Chen. PhD, USF Health Associate Professor of Molecular Medicine with expertise in structured drug design. “Metaphorically, it’s like killing two birds with one stone.”
USF Health-University of Arizona (UA) staff drew on previous work that identified and analyzed several promising antiviral drugs as candidates for the treatment of COVID-19. All candidates selected to pursue the M.professional Blocks SARS-CoV-2 replication in human cells grown in the laboratory.
Two of the compounds, calpain II and XII inhibitors, did not show the same activity against M.professional as another drug candidate named GC-376 in biochemical tests. However, calpain inhibitors, particularly XII, actually worked better than GC-376 in killing SARS-CoV-2 in cell cultures, said lead author Michael Sacco, a doctoral student in Dr. Chen.
“We thought that if these calpain inhibitors were less effective at blocking the virus’s main protease, they would have to do something else to explain their antiviral activity,” Sacco said. They learned from research by other groups, including UA collaborator and co-lead researcher Jun Wang, PhD, that calpain inhibitors can block other proteases, including cathepsin L, a critical human host protease that is involved in the mediation of SARS. -CoV-2 involves entry into cells.
In this latest study, USF Health researchers used advanced techniques, most notably X-ray crystallography, to visualize how calpain II and XII inhibitors interact with the viral M protein.professional. They observed that the calpain II inhibitor inserted into the target binding sites on the surface of the main SARS-CoV-2 protease as expected. Unexpectedly, they also found that the calpain inhibitor XII adopted a unique configuration – known as the “reverse bond pose” – to fit M.professional active binding sites. (Good adaptation optimizes the interaction of the inhibitor with the target virus protein and reduces the enzymatic activity that contributes to the proliferation of SARS-CoV-2.)
“Our findings provide useful structural insights into how we can develop better inhibitors to target this important viral protein in the future,” said Dr. Chen.
In addition to the increased efficacy (desired pharmacological effect at a lower dose) of targeting both viral M.professional and human protease cathepsin L, another benefit of double inhibitors is their potential to suppress drug resistance, said Dr. Chen.
SARS-CoV-2 can mutate or modify its targeted genetic sequence. These viral mutations cause the human cell to attach to the surface membrane of the cell and insert its genetic material, and can change the shape of viral proteins and how they interact with other molecules (including inhibitors) in the cell.
If the virus mutates so that it can continue to multiply, it can become resistant to a particular inhibitor, reducing the effectiveness of that compound. In other words, if the genetic sequence of the viral target (lock) changes, the key (inhibitor) will no longer match that specific lock. Suppose the same key can open two locks to prevent COVID-19 infection. In this case the two locks are M.professionalthe viral target protein and cathepsin L the human target protein.
“It is more difficult for the virus to change both barriers (two drug targets) at the same time,” said Dr. Chen. “A double inhibitor makes it difficult to develop resistance to antiviral drugs because this type of compound remains effective against the unchanged human host protein even if the viral protein changes.”
The USF Health-University of Arizona research team continues to optimize existing antiviral drugs candidates for iMprofessionalWe hope to apply what we have learned to develop new COVID-19 drugs. Your next steps include resolving the chemical and structural interaction of calpain inhibitors with cathepsin L.
Jun Wang, PhD, UA Associate Professor of Pharmacology and Toxicology, was the corresponding author of the Advances in science Paper, along with Dr. Chen as a co-author. The work was supported in part by grants from the National Institutes of Health.
USF Health’s mission is to imagine and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the Taneja College of Pharmacy, the School of Physical Therapy and Rehabilitation Sciences, the Graduate and Postdoctoral Programs of Biomedical Sciences and USF Health’s Group of medical specialists. The University of South Florida is a highly effective global research university dedicated to student success. Over the past 10 years, no other public university in the country has grown faster than the USF in the US News and World Report national university rankings. For more information, see health.usf.edu.
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