A drug called montelukast, approved by the US Food and Drug Administration (FDA), has been around for more than 20 years and is commonly prescribed to reduce inflammation caused by conditions such as asthma, hay fever, and hives.
In the study, published in eLife, researchers showed that the drug binds strongly to one end (the ‘C-terminal’) of a SARS-CoV-2 protein called Nsp1, one of the first viral proteins to spread inside human cells. . This protein can bind to ribosomes – the protein-making machinery inside our immune cells – and shut down the synthesis of important proteins needed by the immune system, leaving it vulnerable. Therefore targeting Nsp1 may reduce the damage caused 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 Tanveer Hussain, assistant professor in the Department of Molecular Breeding, Evolution and Genetics (MRDG), IISc. and senior author of the study. Since NSP1 is likely to remain largely unchanged in any form of the virus that emerges, drugs targeting this region are expected to work against all such forms, he said.
Hussain and his team used computational modeling for the first time to screen more than 1,600 FDA-approved drugs to find drugs that strongly bind to NSP1. Of these, they were able to shortlist a dozen drugs, including montelukast and saquinavir, an anti-HIV drug. “Molecular dynamic simulations generate a lot of data in the range of terabytes, and help to understand the stability of drug-bound protein molecules. Analyzing these and identifying which drugs may act inside the cell is a challenge.” It was,” says Mohamed Afshar, a former project scientist at MRDG, currently a postdoc at the University of Texas at Austin and first author of the study.
Working with associate professor Sandeep Eshwarappa’s group in the Department of Biochemistry, Hussain’s team cultured human cells that specifically produced NSP1, separately treated with montelukast and saquinavir, in the laboratory. and found that only montelukast was able to save the blockage. Protein synthesis by Nsp1.
“There are two sides [to consider]One is affinity and the other is stability,” explains Afshar. This means that the drug not only needs to bind strongly to the viral protein, but also for a sufficiently long time to prevent the protein from affecting the host cell. “The anti-HIV drug (saquinavir) showed good affinity, but not good stability.” Montelukast, on the other hand, was found to bind strongly and strongly to Nsp1, allowing host cells to resume normal protein synthesis can do
Hussain’s laboratory 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 CIDR Assistant Professor Shashank Tripathi and his collaboration. Team. They found that the drug was able to reduce the viral numbers in infected cells in culture.
“Clinicians have tried to use the drug … and there are reports that montelukast has reduced hospitalizations in COVID-19 patients,” says Hussain. His team plans to work with chemists to see if they can modify the drug’s structure to make it more potent against SARS-CoV-2. They also plan to continue hunting for similar drugs with stronger antiviral activity.