Since the COVID-19 pandemic began, research has been carried out to develop vaccines that would prevent the spread of SARS-CoV-2 or reduce the severity of COVID-19 symptoms, and part of the scientific research has been aimed at evaluating the effectiveness of other drugs that had already been approved to treat other health problems in combating this infectious disease. This has been the case of montelukast, a drug for the treatment of asthma from which some batches have recently been withdrawn in Spain, after the Spanish Medicines Agency detected some impurities.
Montelukast, which began to be marketed more than 20 years ago and is used to reduce inflammation caused by asthma, hives or hay fever, could also be useful in combating coronavirus infection, since a new study that has been published published in eLife has shown that it is capable of binding to a key protein produced by SARS-CoV-2 and blocking it, reducing the replication of the virus in human immune cells.
The research that has discovered this quality of the drug has been carried out by scientists from the Indian Institute of Sciences (IISc), who have verified that it binds strongly to one end (‘C-terminal’) of a SARS-CoV-2 protein called Nsp1, which is one of the first viral proteins released inside human cells and can bind to ribosomes – which are responsible for producing proteins inside our immune cells – and stop the synthesis of vital proteins needed by the immune system, weakening it . Therefore, targeting Nsp1 could decrease the damage caused by the coronavirus.
“The mutation rate in this protein, especially in the C-terminal region, is very low compared to other viral proteins,” explains Tanweer Hussain, Assistant Professor in the Department of Molecular Reproduction, Development and Genetics (MRDG), IISc, and lead author of the study, who adds that Nsp1 is likely to remain virtually unchanged in any variant of the virus that appears, so drugs targeting this region are expected to be effective against all such variants.
Montelukast reduced the number of viruses in infected cells
Hussain and his team began by using computational modeling to screen more than 1,600 FDA-approved drugs to identify those that strongly bound Nsp1. From among them, they were able to shortlist a dozen drugs, including montelukast and saquinavir, an anti-HIV drug.
Nsp1 is likely to remain almost unchanged in any variant of the coronavirus, so drugs targeting this protein would be effective against all of them.
“Molecular dynamics simulations generate a large amount of data, in the terabyte range, and help determine the stability of the drug-bound protein molecule. Analyzing them and identifying which drugs can 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, and first author of the study.
Hussain’s team, in collaboration with the group of Sandeep Eswarappa, Associate Professor in the Department of Biochemistry, grew human cells in the lab that specifically produced Nsp1, treated them with montelukast and saquinavir separately, and found that only montelukast could rescue the inhibition of protein synthesis by Nsp1.
“There are two aspects [a considerar]: one is affinity and the other is stability”, says Afsar. This means that the drug must not only bind tightly to the viral protein, but also remain bound for a long enough time to prevent the protein from affecting the host cell, he continues. “The HIV drug (saquinavir) showed good affinity, but not good stability.” Montelukast, on the other hand, strongly and stably bound Nsp1, allowing host cells to resume normal protein synthesis.
Hussain’s lab then tested how the drug worked on live viruses, at the Bio-Safety Level 3 (BSL-3) facility at the Center for Infectious Diseases Research (CIDR), IISc, in collaboration with Shashank Tripathi, Professor Assistant at CIDR, and his team. They found that montelukast was able to reduce the number of viruses in infected cells in culture.
“Physicians have tried using the drug … and there are reports that montelukast reduced hospitalization in COVID-19 patients,” says Hussain, adding that more research is needed to better understand the exact mechanisms by which it occurs. works. The intention of his team is now to work with chemists to see if they can modify the structure of the drug to make it more powerful against SARS-CoV-2, in addition to continuing to search for similar drugs with potent antiviral activity.
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