Indian Study Adds More Evidence That The Asthma Drug Montelukast (Singulair) Can Inhibit SARS-CoV-2 Replication And Is A Potential COVID-19 Drug!
: Researchers from the Indian Institute of Science, India has found that the asthma drug Montelukast (Singulair) can block the SARS-CoV-2 non-structural protein 1 (Nsp1,) which in turn results in the inhibition of SARS-CoV-2 replication, showing it prowess as potential COVID-19 drug!
Montelukast is a drug used in the maintenance treatment of asthma that is marketed under the trade name Singulair and others. It typically decreases the symptoms and the number of acute asthma attacks. However, this medicine should not be used to relieve an asthma attack that has already started and it is not useful for acute asthma attack. In general, it is less favored for this application than inhaled corticosteroids. It is ineffective in treating acute asthma attacks. Other applications include allergic rhinitis and long-lasting hives. It is a second-line therapy for allergic rhinitis.
Montelukast belongs to the leukotriene receptor antagonist family of medications. It works by blocking the action of leukotriene D4 in the lungs resulting in decreased inflammation and relaxation of smooth muscle. It basically functions as a leukotriene receptor antagonist (cysteinyl leukotriene receptors) and consequently opposes the function of these inflammatory mediators; leukotrienes are produced by the immune system and serve to promote bronchoconstriction, inflammation, microvascular permeability, and mucus secretion in asthma and COPD. Leukotriene receptor antagonists are sometimes colloquially referred to as leukasts.
It is already known that the SARS-CoV-2 non-structural protein 1 (Nsp1) contains an N-terminal domain and C-terminal helices connected by a short linker region. The C-terminal helices of Nsp1 (Nsp1-C-ter) from SARS-CoV-2 bind in the mRNA entry channel of the 40S ribosomal subunit and blocks mRNA entry, thereby shutting down host protein synthesis.
The Nsp1 protein basically suppresses host immune function and is vital for viral replication. Hence, Nsp1 appears to be an attractive target for therapeutics.
The study team in silico screened Food and Drug Administration (FDA)-approved drugs against Nsp1-C-ter. Among the top hits obtained, montelukast sodium hydrate binds to Nsp1 with a binding affinity (KD) of 10.8 ± 0.2 µM in vitro. It forms a stable complex with Nsp1-C-ter in simulation runs with –95.8 ± 13.3 kJ/mol binding energy.
Montelukast sodium hydrate also rescues the inhibitory effect of Nsp1 in host protein synthesis, as demonstrated by the expression of firefly luciferase reporter gene in cells. Importantly, it shows antiviral activity against SARS-CoV-2 with reduced viral replication in HEK cells expressing ACE2 and Vero-E6 cells.
The COVID-19 Drugs
study team therefore, proposed that montelukast sodium hydrate could be used as a lead molecule to design potent inhibitors to help combat SARS-CoV-2 infection.
The study findings were published in the peer reviewed journal: eLife.
Approved by the US Food and Drug Administration (FDA), montelukast, has been around for more than 20 years and is typically prescribed to reduce inflammation caused by conditions like asthma, hives
, and hay fever.
A number of past studies have already showed that it had the potential or was effective to treat COVID-19 and even long COVID.
Interestingly, one study showed that montelukast inhibits platelet activation induced by plasma from COVID-19 patients. https://www.frontiersin.org/articles/10.3389/fphar.2022.784214/full
A recent clinical trial by American researchers from Rutgers University, New Brunswick, NJ has found that hospitalized COVID-19 patients treated with montelukast had fewer events of clinical deterioration, indicating that this treatment may have clinical activity. https://pubmed.ncbi.nlm.nih.gov/33577360/
The Indian researchers in the current study 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 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. Targeting Nsp1 could therefore reduce the damage inflicted by the virus.
Senior author, Dr Tanweer Hussain, Assistant Professor in the Department of Molecular Reproduction, Development and Genetics (MRDG), IISc told Thailand Medical News
, “The mutation rate in this protein, especially the C-terminal region, 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 first used computational modeling 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.
First author, Dr Mohammad Afsar, former Project Scientist at MRDG, currently a postdoc at the University of Texas at Austin added, “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.”
Together by working with the group of Dr Sandeep Eswarappa, Associate Professor in the Department of Biochemistry, Dr Hussain’s team then cultured human cells in the lab that specifically produced Nsp1, treated them with montelukast and saquinavir separately, and found that only montelukast was able to rescue the inhibition of protein synthesis by Nsp1.
Dr Afsar explained, “There are two aspects to consider: 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 tested the effect of the drug on live viruses, in the Bio-Safety Level 3 (BSL-3) facility at the Centre for Infectious Disease Research (CIDR), IISc, in collaboration with Dr Shashank Tripathi, Assistant Professor at CIDR, and his team. The study team found that the drug was able to reduce viral numbers in infected cells in the culture.
Dr Hussain commented, “Clinicians have tried using the drug and there are reports that said that montelukast reduced hospitalization in COVID-19 patients.”
He however added 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 modify the structure of the drug to make it more potent against SARS-CoV-2. They also plan to continue hunting for similar drugs with strong antiviral activity.
It should be noted that Montelukast has antiviral effects as it was also able to inhibits the Zika virus infection by disrupting viral integrity. https://www.frontiersin.org/articles/10.3389/fmicb.2019.03079/full
However, Thailand Medical News
is a bit skeptical as to whether Montelukast will work against the newly emerged BA.2 and BA.4 sub-variants which as a result of lengthy but rapid evolution are sporting a lot of missense mutations in the Mpro section of the ORF1a/b gene and also in the nsp1 proteins. Detailed research is required to assess its efficacy against these new emerging and fast becoming dominant variants. https://www.thailandmedical.news/news/warning-mutations-in-new-emerging-ba-2,-ba-4-subvariants-are-changing-the-main-coronavirus-protease-drastically,-rendering-many-previous-antivirals-ob
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