The drug not only binds strongly to the viral protein but also stops the protein from harming the host cell, allowing the host cells to continue with normal protein synthesis.

Researchers from India’s Indian Institute of Science discovered that the asthma medicine Montelukast (Singulair) can disrupt the SARS-CoV-2 non-structural protein 1 (Nsp1), which inhibits SARS-CoV-2 replication, indicating its potential as a COVID-19 treatment.

Montelukast is a medication used under the brand name Singulair and others for the continuous treatment of asthma. It usually reduces the severity of symptoms as well as the number of acute asthma attacks. This medicine, on the other hand, should not be used to treat an asthma attack that has already begun, and it is ineffective for acute asthma attacks. In general, it is not as effective as inhaled corticosteroids in this application. In the treatment of acute asthma attacks, it is unsuccessful. Other uses include allergic rhinitis and chronic hives. It is used to treat allergic rhinitis as a second-line treatment.

Montelukast belongs to the class of drugs known as leukotriene receptor antagonists. It acts by inhibiting the function of leukotriene D4 in the lungs, resulting in less inflammation and smooth muscle relaxation. It works as a leukotriene receptor antagonist (cysteinyl leukotriene receptors) and blocks the function of these inflammatory mediators. Leukotrienes are produced by the immune system and improve bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD patients. Leukasts are a term used to describe antagonists of leukotriene receptors.

The N-terminal domain and C-terminal helices of the SARS-CoV-2 non-structural protein 1 (Nsp1) are known to be connected by a short linker region. The C-terminal helices of SARS-CoV-2 Nsp1 (Nsp1-C-ter) engage in the 40S ribosomal subunit’s mRNA entry channel, blocking mRNA entrance and shutting down host protein synthesis.

The Nsp1 protein is required for viral replication and reduces host immune activity. As a result, Nsp1 appears to be a promising therapeutic target.

The researchers evaluated FDA-approved medicines against Nsp1-C-ter in a computer simulation. Montelukast sodium hydrate, one of the top hits, binds to Nsp1 in vitro with a binding affinity (KD) of 110.8 ± 0.2 µM. In simulation runs, it forms a stable complex with Nsp1-C-ter with a binding energy of –95.8 ± 13.3 kJ/mol.

The production of the firefly luciferase reporter gene in cells also shows that Montelukast sodium hydrate reverses Nsp1’s inhibitory effect on host protein synthesis. It also inhibits viral replication in HEK cells expressing ACE2 and Vero-E6 cells, indicating antiviral efficacy against SARS-CoV-2.

That’s why the COVID-19 Drugs study team said montelukast sodium hydrate could be a good lead molecule to help fight SARS-CoV-2 infection.

The findings of the study were published in eLife, a peer-reviewed journal.

Montelukast, which has been approved by the US Food and Drug Administration (FDA), has been used to treat inflammation caused by illnesses such as asthma, hives, and hay fever for more than 20 years.

Several previous trials have already demonstrated that it has the ability to treat COVID-19 and even long COVID.

One study found that montelukast can even stop platelets from getting activated by plasma from COVID-19 patients.

According to a recent clinical trial conducted by Rutgers University in New Brunswick, NJ, hospitalized COVID-19 patients treated with montelukast had fewer occurrences of clinical deterioration, indicating that this medication may have therapeutic activity.

The present investigation by Indian researchers demonstrated that the medication significantly binds to one end (‘C-terminal’) of a SARS-CoV-2 protein termed Nsp1, one of the first viral proteins to be released within human cells. This protein can bind to ribosomes (protein-making machinery) inside immune cells, halting the production of critical proteins needed by the immune system and therefore weakening it. As a result, targeting Nsp1 may help to decrease the virus’s damage.

“The mutation rate in this protein, especially the C-terminal region,” according to Senior author, Dr Tanweer Hussain, “is very low compared to the rest of the viral proteins. 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.”

Dr. Hussain and his team used computational modeling to evaluate over 1,600 FDA-approved medicines to identify those that bind to Nsp1 strongly. They were able to shortlist a dozen medications, including montelukast and saquinavir, an anti-HIV treatment, based on these results.

“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 analyze these and identify which drugs may work inside the cell was a challenge.”

To do so, the researchers cultivated Nsp1-producing human cells in the lab, treated them with montelukast and saquinavir separately, and discovered that only montelukast could reverse Nsp1’s suppression of protein synthesis.

“There are two aspects to consider,” according to authors, “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.

“The anti-HIV drug: saquinavir showed good affinity, but not good stability. Montelukast, on the other hand, was found to bind strongly and stably to Nsp1, allowing the host cells to resume normal protein synthesis.”

The study team then investigated the drug’s effect on live viruses in the Bio-Safety Level 3 (BSL-3) facility at IISc’s Centre for Infectious Disease Research (CIDR). The researchers discovered that the medication reduced viral numbers in infected cells in the culture.

“Clinicians have tried using the drug and there are reports that said that montelukast reduced hospitalization in COVID-19 patients,” the authors added.

They did note, however, that the particular methods by which it works are still unknown. The team intends to collaborate with scientists to see if they can improve the drug’s structure to make it more effective against SARS-CoV-2. They also intend to keep looking for similar medicines with potent antiviral properties.

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