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SARS-CoV-2, the respiratory virus that causes COVID-19, attacks the body in several steps. 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.
A new study provides insight into antiviral drug design for COVID-19 by demonstrating that some existing compounds contain both the main protease (Mpro), a key viral protein required for SARS-CoV-2 replication in human cells, and can inhibit lysosomal protease cathepsin L, a human protein important for virus entry into host cells. The study, led by researchers at the University of South Florida Health’s Morsani College of Medicine (USF Health) and the University of Arizona Health College of Pharmacy, was published today in Science Advances.
“If we can develop compounds to significantly deactivate or reduce both processes – virus entry and virus replication – such double inhibition can improve the effectiveness of these compounds in treating coronavirus infection,” the co-director said. lead researcher on the study, Yu Chen, Ph.D., Associate Professor of Molecular Medicine at USF Health 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 Mpro goal of blocking 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 Mpro in biochemical tests as another drug candidate called GC-376. 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 are less effective at inhibiting the virus’ main protease, they need 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, Ph.D., that calpain inhibitors can block other proteases, including cathepsin L, a critical human host protease that is implicated in SARS mediation is. CoV-2 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 protein Mpro. 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 XII inhibitor adopted a unique configuration – known as the “inverted binding position” – to perfectly match the active binding sites of Mpro. (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 results provide useful structural insights into how we can design 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 fighting both the viral protease Mpro and the human cathepsin L protease, 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.
When 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 barriers are Mpro, the 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 fine-tune existing antiviral drugs candidates to improve their stability and performance, and hopes to apply what they learn in the development of new COVID-19 drugs. Your next steps include resolving the chemical and structural interaction of calpain inhibitors with cathepsin L.
Supplied by
University of South Florida.
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