NEW DELHI, Apr 26: A drug used to treat asthma and allergies can reduce replication of SARS-COV-2 in human immune cells by blocking a crucial protein produced by the virus, according to a study by researchers at the Indian Institute of Science (IISc) – Bengaluru.
The drug, called montelukast, is approved by the US Food and Drug Administration (FDA) and has been around for more than 20 years, the researchers said.
Montelukast is usually prescribed to reduce inflammation caused by conditions like asthma, hay fever and hives, they said.
The study, published in the journal eLife on Monday, shows that the drug binds strongly to one end of a SARS-CoV-2 protein called Nsp1, which is one of the first viral proteins unleashed inside the human cells.
This protein can bind to ribosomes — the protein-making machinery — inside our immune cells and shut down the synthesis of vital proteins required by the immune system, thereby weakening it, the researchers said.
Targeting Nsp1 could therefore reduce the damage inflicted by the virus, they said.
“The mutation rate in this protein is very low compared to the rest of the viral proteins,” said Tanweer Hussain, Assistant Professor in the Department of Molecular Reproduction, Development and Genetics (MRDG), IISc, and senior author of the study.
Since Nsp1 is likely to remain largely unchanged in any variants of the virus that emerge, drugs targeting this region are expected to work against all such variants, Hussain added.
The research team first used computational modelling to screen more than 1,600 FDA-approved drugs in order to find the ones that bound strongly to Nsp1.
From these, they were able to shortlist a dozen drugs including montelukast and saquinavir, an anti-HIV drug.
“The molecular dynamic simulations generate a lot of data, in the range of terabytes, and help to figure out the stability of the drug-bound protein molecule. To analyse these and identify which drugs may work inside the cell was a challenge,” said Mohammad Afsar, former Project Scientist at MRDG, currently a postdoc at the University of Texas at Austin, US, and first author of the study. Working with the group of Sandeep Eswarappa, Associate Professor in the Department of Biochemistry, Hussain’s team cultured human cells in the lab that specifically produced Nsp1.
The team treated these cells with montelukast and saquinavir separately, and found that only montelukast was able to rescue the inhibition of protein synthesis by Nsp1.
“There are two aspects: one is affinity and the other is stability. This means that the drug needs to not only bind to the viral protein strongly, but also stay bound for a sufficiently long time to prevent the protein from affecting the host cell,” Afsar said.
“The anti-HIV drug (saquinavir) showed good affinity, but not good stability,” he added.
Montelukast, on the other hand, was found to bind strongly and stably to Nsp1, allowing the host cells to resume normal protein synthesis, the researchers said.
Hussain’s lab then tested the effect of the drug on live viruses at the Centre 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 the culture.
“Clinicians have tried using the drug … and there are reports that said that montelukast reduced hospitalisation in COVID-19 patients,” said Hussain, adding that the exact mechanisms by which it works still need to be fully understood.
The team plans to work with chemists to see if they can modify the structure of the drug to make it more potent against SARS-CoV-2. (PTI)
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