A drug used to treat asthma and allergies can bind and block an important protein produced by the SARS-CoV-2 virus and reduce the virus’s replication in human immune cells, according to a new study by researchers at the Indian Institute of Science (IISc). ). ).
Approved by the US Food and Drug Administration (FDA), a drug called montelukast has been around for more than 20 years and is usually prescribed to reduce inflammation caused by conditions such as asthma, hay fever and hives, according to the official publication of IISC. on Monday.
In a study published in eLife, researchers showed that the drug binds strongly to one end (“C-terminal”) of a SARS-CoV-2 protein called Nsp1, which is one of the first viral proteins released in human cells. This protein can bind to the ribosomes – the protein-producing machine – inside our immune cells and stop the synthesis of vital proteins needed by the immune system, thus weakening it. Therefore, targeting Nsp1 can reduce the damage caused by the virus.
“The rate of mutations in this protein, especially in the C-terminal region, is very low compared to other viral proteins,” said Tanvier Hussein, an assistant professor in the Department of Molecular Reproduction, Development and Genetics (MRDG), IISc, and senior author of the study. As Nsp1 is likely to remain largely unchanged in all variants of the virus that are emerging, drugs targeting the region are expected to work against all such variants, he added.
Hussein and his team first used computational modeling to screen more than 1,600 FDA-approved drugs to find those that are strongly associated with Nsp1. From them, they managed to choose a dozen drugs, including montelukast and saquinavir, an anti-HIV drug.
“Molecular dynamic simulations generate a lot of data in the terabyte range and help to understand the stability of a drug-related protein molecule. Analyzing these and identifying which drugs can work inside the cell was a challenge, “said Mohammad Afsar, a former project scientist at MRDG, currently a postdoc at the University of Texas at Austin and the lead author of the study.
Working with the Sandeep Eswarappa team, an associate professor in biochemistry, the Hussain team then cultured human cells in the laboratory that specifically produce Nsp1, treated them with montelukast and saquinavir separately, and found that montelukast alone could save protein inhibition. synthesis from Nsp1.
“There are two aspects that need to be taken into account: one is affinity and the other is stability,” Afsar said. This means that the drug must not only bind strongly to the viral protein, but also remain bound long enough to prevent the protein from affecting the host cell, he added. “The anti-HIV drug (saquinavir) showed good affinity, but not good stability.” 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 Level 3 Biosafety Facility (BSL-3) at the Center for Infectious Diseases Research (CIDR), IISc, in collaboration with Shashank Tripathi, assistant professor at CIDR, and his team. They found that the drug was able to reduce the number of viruses in infected cells in culture.
“Clinicians have tried to use the drug and there are reports that montelukast reduces hospitalizations among patients with Covid-19,” said Hussein, 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 change the structure of the drug to make it more potent against SARS-CoV-2. They also plan to continue looking for similar drugs with strong antiviral activity.
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