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Research shows a strategy to create a drug COVID-19 to inhibit viral penetration and replication



Research shows a strategy to create a drug COVID-19 to inhibit viral penetration and replication

The X-ray crystal structure of the main protease of SARS-CoV-2 interacts with a calpaine XII inhibitor (blue). The antiviral compound has been shown to use an atypical configuration, called the backlink posture, to fit the targeted viral protein binding site. Imaging Provider: Michael Sacco of USF Health, using X-ray crystallography method.

SARS-CoV-2, the respiratory virus that causes COVID-1

9, attacks the body in several steps. Getting into cells deep in the lungs and taking control of the human host cell machinery to make copies of itself are two of the earliest steps – both of which are required for microbial infection. -withdraw.

A new study provides insight into the design of antiviral drugs against COVID-19 by showing that several existing compounds can inhibit even the main protease (Mprofession), an important viral protein required for the replication of SARS-CoV-2 inside human cells, and the protease cathepsin L lysosome, a human protein important for virus entry into host cells. The study was led by researchers at the University of Health of South Florida (USF Health), Morsani Medical College and Arizona College of Pharmacy, announced today in Scientific advance.

“If we could develop compounds to halt or significantly reduce both processes – viral infiltration and viral replication – such double-inhibitions could enhance the efficacy of these two processes. this compound in the treatment of coronavirus infection, ”said co-researcher Yu Chen, Ph.D., associate professor of molecular medicine at USF Health with expertise in structural drug design. “Metaphorically speaking, it’s like killing two birds with one stone.”

The collaborators of USF Health-University of Arizona (UA) built on their previous work, identifying and analyzing a number of existing antiviral drugs, promising candidates for COVID-19 treatment. All candidates are selected to pursue Mprofession to prevent the replication of SARS-CoV-2 in human cells grown in the laboratory.

Two of the compounds, calpain II and XII inhibitors, do not have much activity against Mprofession as another drug candidate is called GC-376 in biochemical tests. However, calpain inhibitors, particularly XII, actually outperformed GC-376 in killing SARS-CoV-2 in cell culture, Michael Sacco, a PhD student in the lab. of Dr. Chen, said.

“We found that if these calpain inhibitors were less effective at inhibiting the virus’s main protease, they had to do something else to explain their antiviral activity,” Sacco said. They learned from research done by other groups, including collaborator and co-investigator Jun Wang, Ph.D., of the UA, that calpain inhibitors can block other proteases, This includes cathepsin L, an important human host protease involved in the SARS-CoV-2 intermediary that enters the cell.

Research shows a strategy to create a drug COVID-19 to inhibit viral penetration and replication

Lead author Michael Sacco (sitting), a doctoral student at the USF Health Department of Molecular Medicine, with study co-investigator Yu Chen, Ph.D., in Dr. Chen’s lab at Southern University Florida. Credit: USF Health / University of South Florida

In this latest study, USF Health researchers used advanced techniques, especially X-ray crystallography, to visualize how calpain II and XII inhibitors interact with proteins in the M virus.profession. They observed that the calpain II inhibitor was expected to conform to the targeted binding sites on the surface of the primary protease SARS-CoV-2. Unexpectedly, they also found that the XII calpaine inhibitor used a unique configuration – called the “backlink posture” – to fit M.profession Active affiliate sites. (A well-fitting jacket optimizes the inhibitor’s interaction with the targeted viral protein, reducing the enzyme activity that helps SARS-CoV-2 proliferate.)

“Our findings provide useful structural information on how we could design better inhibitors to target this important viral protein in the future,” said Dr. Chen.

In addition to an increased potency (desirable drug effect at lower doses) against the protease M of the virusprofession and human cathepsin L protease, another benefit of the dual inhibitors is their ability to prevent resistance, Dr. Chen said.

SARS-CoV-2 may mutate or alter its targeted genetic sequence. These viral mutations trick the human cell into allowing the virus to attach to the cell’s surface membrane and insert its genetic material, while also altering the shape of viral proteins and how they interact with the feces. Other particles (including inhibitors) inside the cell.

When the virus mutates so it can continue to reproduce, it can become resistant to a specific inhibitor, reducing the compound’s effectiveness. In other words, if the genetic sequence of the target (blocking) the virus changes, the lock (inhibitor) no longer matches that particular key. But suppose the same key could open two locks to help prevent COVID-19 infection; in this case the two keys are Mprofession, viral target protein, and cathepsin L, human target protein.

“It’s hard for the virus to change both locks (two drug targets) at the same time,” said Dr. Chen. “Therefore, a dual inhibitor makes antiviral resistance more difficult to develop, because even if the virus’s protein changes, this compound is still effective against the host protein. man without changing. “

The USF Health-University of Arizona team continues to refine existing antiviral drug candidates into iMprofessionin terms of their stability and performance, and hopefully apply what they have learned to help design new COVID-19 drugs. Their next steps will include addressing how the calpaine inhibitor chemically and structurally interacts with cathepsin L.


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More information:
Structure and inhibition of the primary protease SARS-CoV-2 shows a strategy of developing dual inhibitors against Mpro and cathepsin L, Scientific advance (Year 2020). Progress.sciencemag.org/lookup… .1126 / sciadv.abe0751

Provided by University of South Florida

Quote: Research revealing strategy to create COVID-19 drug to inhibit virus penetration and replication (2020, November 6) retrieved November 7, 2020 from https: // medicalxpress. com / news / 2020-11-reveals-strategy-covid-drugs-inression .html

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