The drug Montelukast can bind to and block a crucial protein produced by the virus SARS-CoV-2


A drug used to treat asthma and allergies can bind to and block a crucial protein produced by the virus SARS-CoV-2, and reduce viral replication in human immune cells, according to a new study by researchers at the Indian Institute of Science (IISc).

Approved by the U.S. Food and Drug Administration (FDA), the drug, called montelukast, has been around for more than 20 years and is usually prescribed to reduce inflammation caused by conditions like asthma, hay fever and hives.

In the study, published in eLife, the researchers show 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.

“The mutation rate in this protein, especially the C-terminal region, is very low compared to the rest of the viral proteins,” explains 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, he adds.

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.

“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,” says Mohammad Afsar, former Project Scientist at MRDG, currently a postdoc at the University of Texas at Austin, and first author of the study.

Working with the group of Sandeep Eswarappa, Associate Professor in the Department of Biochemistry, 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.

“There are two aspects [to consider]: one is affinity and the other is stability,” explains Afsar. 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, he adds. “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.

Hussain’s lab 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 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 hospitalization in COVID-19 patients,” says Hussain, adding 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.

The objective of this retrospective study was to evaluate the efficacy of montelukast in preventing clinical deterioration among patients hospitalized with COVID-19. Clinical deterioration was measured by changes in the COVID-19 Ordinal Scale. Oxygen escalation occurred in 32% of patients without montelukast versus 10% of patients taking montelukast.

This was evident despite the montelukast group being of significantly older age (p = 0.022). Furthermore, patients receiving montelukast had higher rates of baseline asthma and tended to have more cardiac comorbidities, potentially suggesting these patients had increased risk for clinical decompensation during COVID-19 infection.

These findings suggest that montelukast may have clinical efficacy in reducing complications of COVID-19. With further evaluation, montelukast may be a potential therapy for COVID-19 infection.

We examined the effects of montelukast on laboratory values associated with COVID-19 illness and found no differences in inflammatory laboratory values including CRP, D-dimer, ferritin, and LDH between montelukast versus non-montelukast patients. It is feasible that there were, in fact, no differences in the trends of laboratory values between patients treated with montelukast vs. non-montelukast.

However, given the lack of a method to grade these particular laboratory values, the differences in these values could not be accurately compared among patients. We anticipate that the laboratory values of patients could be impacted by montelukast, but we were unable to derive an answer in this dataset.

In addition, a limitation to this study was the lack of specific systemic or pulmonary cytokine measurements or serial SARS-CoV-2 viral loads that may better reflect the potential effect of montelukast on virally-mediated pathways in SARS-CoV-2 infection. We found no difference in length of hospitalization between the two groups. However, we considered length of stay a subjective indicator of clinical outcome as there is no standardization between physician practices for decisions surrounding discharge time and planning.

Montelukast is a leukotriene receptor antagonist and binds with high affinity and selectivity to the CysLT1 receptor (cysteinyl leukotriene). Eicasanoids including all cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from cells including mast cells and eosinophils (12).

These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors, which are found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (12). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis (12).

In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. Furthermore, clinical findings indicate that montelukast can be used in the effective management of acute and post viral-induced wheezing, and it can quickly improve respiratory function in acute asthmatic patients with an increased FEV1 at 60-min post-montelukast administration and at all time points up to 120 min (n = 583) (13,14).

Another study documented data that asthmatic children treated with montelukast had higher lung function, decreased airway inflammation, and lower symptom scores compared with the children not receiving montelukast (15). While baseline asthma has not been found to be a risk factor for severe outcomes in COVID-19, other comorbidities such as hypertension and diabetes have been correlated with worse prognosis (16,17). In our study, 15 patients had a baseline diagnosis of asthma, 11 of whom received montelukast during hospitalization.

The progression of COVID-19 infection to severe clinical complications is thought to be due to ARDS and a hyperinflammatory cytokine syndrome, or cytokine storm (18). Secondary hemophagic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome leading to a fulminant and fatal hypercytokinemia with multiorgan failure in the setting of viral infections, and demonstrates unremitting fever, cytopenias, and hyperferritinemia; pulmonary involvement including ARDS occurs in 50% of patients (18).

Cytokine profiles having sHLH resemble COVID-19 disease severity, with increased IL-2, IL-7, GM-CSF, IFN-gamma-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-alpha, and tumor necrosis factor alpha (18). Viral hyperinflammation appeared to drive COVID-19 fatalities in Wuhan, China, and predictors of mortality from COVID-19 cases in Wuhan included an elevated ferritin (1297.6 ng/mL in non-survivors vs. 614 ng/mL in survivors, p < 0.001), suggesting that fatalities are driven by viral hyperinflammation (18). NF-KB (nuclear factor kappa-light-chain-enhancer of activated B cells) can regulate immune responses, and its inhibition by MTK may attenuate the symptoms of COVID-19 by downregulating other inflammatory cytokines such as IL-6 and IL-8, mitigating the severity of infection and decreasing symptoms (19).

We noted that treatment with montelukast had interesting results in subpopulations of interest. Sensitivity analysis among those without asthma showed a trend toward fewer events of clinical deterioration in the montelukast group compared with the non montelukast group. While montelukast is commonly used an asthma maintenance therapy, our results suggest a benefit of montelukast independent from that found in its traditional use in asthma. Sensitivity analysis among those who received steroids did not reveal a difference in clinical deterioration events. Thus, co-administration may have blunted the anti-inflammatory effects of montelukast.

The standard dosing of montelukast is 10 mg orally per day for allergic rhinitis, asthma, and prevention of exercise-induced asthma. Montelukast has a favorable side effect profile with limited toxicities, indicating the potential to evaluate higher doses, with possible relative safety (20).

The most common side effects of montelukast as per the US prescribing information include upper respiratory infection, fever, headache, sore throat, and cough.

Additionally, the US prescribing information includes a boxed warning regarding the risk of neuropsychiatric events with montelukast. Further, Glockler-Lauf et al. published on the association between montelukast use in children and neuropsychiatric events, but there is currently no indication for its use in treating viral symptoms of SARS-CoV-2 infection (21).

Given that montelukast is a well-tolerated and a low-cost agent, information about dose responses in COVID-19 infection could be an important aspect to evaluate new dosing regimens, and could have impact on the duration and severity of symptoms of COVID-19 as well as which patients are most likely to benefit.

These favorable characteristics of montelukast are especially critical during the COVID-19 pandemic, as preventing clinical deterioration can save the use of depleted resources such as intensive care unit beds and mechanical ventilators.

While the results of this retrospective review are encouraging, they are not without limitations. The small sample size, retrospective nature of the study contributing to selection bias, the administration of montelukast as dictated by physician discretion, and limited data points in evaluation warrant further study with a larger prospective sample size. Additionally, a main limitation to our study is the lack of ability to control for multiple potential confounders.

Our findings suggest that montelukast administration can be used to quell clinical deterioration associated with COVID-19 infection. A recently reported retrospective observational study found a statistically significant reduction in confirmed COVID-19 cases among elderly asthmatic patients treated with montelukast (22). Also, it has been hypothesized that montelukast can limit progression of disease for COVID-19 positive patients, specifically in high risk factor obese patients (1,23).

Similar findings for the treatment of COVID-19 infection with montelukast would bolster the support for montelukast as a therapeutic agent for COVID-19. Rather than incorporation into practice without further study, we advocate for confirmatory clinical trials and additional retrospective data to support the incorporation of montelukast for the treatment of COVID-19.

One such trial appears to be ongoing, such as NCT04389411, a phase 3 trial evaluating the use of montelukast compared with placebo for COVID-19 infection.

reference link :

More information: Mohammad Afsar et al, Drug targeting Nsp1-ribosomal complex shows antiviral activity against SARS-CoV-2, eLife (2022). DOI: 10.7554/eLife.74877


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