Asthma drug can block important SARS-CoV-2 proteins

Image: Nsp1 targeting with montelukast helps prevent shutdown of host protein synthesis
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Credit: Muhammed Afsar

A new study by researchers at the Indian Institute of Science (IISc) shows that a drug used to treat asthma and allergies can bind to and inhibit the essential protein produced by SARS-CoV-2, reducing virus replication in human immune cells. ).

The drug called montelukast has been approved by the U.S. Food and Drug Administration (FDA), and it’s been around for more than 20 years and is usually prescribed to reduce inflammation caused by conditions such as asthma, hay fever and urticaria.

In the study published in eLifeAnd The researchers showed that the drug strongly binds to one end (“C-terminal”) of a SARS-CoV-2 protein called Nsp1, one of the first viral proteins released into human cells. This protein can bind to ribosomes – the protein-making machinery – within our immune cells and stop the manufacture of vital proteins needed by the immune system, thereby impairing it. Thus, targeting Nsp1 can reduce the damage done by the virus.

“The mutation rate in this protein, especially the C-terminal region, is very low compared to the rest of the viral proteins,” explains Tanweer Hussain, Associate Professor in the Department of Molecular Reproduction, Development and Genetics (MRDG), IIS. and senior author of the study. He adds that because Nsp1 is likely to remain largely unchanged in which variants of the virus appear, drugs targeting this region would be expected to act against all of these variants.

Hussein and his team used computer modeling for the first time to screen more than 1,600 Food and Drug Administration-approved drugs in order to find those strongly associated with Nsp1. Of those, they were able to identify dozens of drugs including montelukast and saquinavir, an anti-HIV drug. “Molecular dynamic simulations generate a lot of data, in the terabyte range, and help figure out the stability of a drug-bound protein molecule. Muhammed Afsar, a former project scientist at MRDG and currently a postdoctoral researcher at the University of Texas at Austin, and first author of the study, says the analysis of These factors and identification of drugs that may act within the cell has been a challenge.

Working with Sandeep Eswarappa’s group, associate professor in the Department of Biochemistry, Hussein’s team then in vitro cultured human cells that specifically produced Nsp1, treated them with montelukast and saquinavir separately, and found that only montelukast was able to rescue the inhibition of protein synthesis by Nsp1.

“There are two sides [to consider]Afsar explains: One is convergence and the other is stability. He adds that this means that the drug not only needs to bind to the viral protein strongly, but also stay bound long enough to prevent the protein from affecting the host cell. “The anti-HIV drug (saquinavir) showed good affinity, but it was not so good.” On the other hand, montelukast was found to bind strongly and stably to Nsp1, allowing host cells to resume normal protein synthesis.

Hussain’s lab then tested the drug’s effect on live viruses, at the Biosafety Level 3 (BSL-3) facility at the Center for Infectious Disease Research (CIDR), IISc, in collaboration with Shashank Tripathi, assistant professor at CIDR, and his team. They found that the drug was able to reduce viral numbers in infected cells in culture.

“Doctors have tried using the drug…and there are reports that montelukast has reduced hospitalizations for COVID-19 patients,” Hussain says, adding that the exact mechanisms by which it works still need to be fully understood. His team plans to work with chemists to see if they can modify the drug’s structure to make it more effective against SARS-CoV-2. They also plan to continue the search for similar drugs with strong antiviral activity.

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