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Tag Archives: Replication
Asthma Drug Montelukast (Singulair) Can Block Crucial COVID Protein, Reducing Viral Replication
Targeting Nsp1 with montelukast (Singulair) helps prevent shutdown of host protein synthesis. Credit: Mohammad Afsar
An oral medication used to treat asthma and allergies can bind to and block a crucial protein produced by the
Montelukast is a drug used in the maintenance treatment of asthma that is marketed under the trade name Singulair and others. 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.
“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
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CRISPR Breakthrough Blocks SARS-CoV-2 Virus Replication in Early Lab Tests
Scientists have used CRISPR gene-editing technology to successfully block the transmission of the SARS-CoV-2 virus in infected human cells, according to research released Tuesday that could pave the way for COVID-19 treatments.
Writing in the journal Nature Communications, researchers in Australia said the tool was effective against viral transmissions in lab tests, adding that they hoped to begin animal trials soon.
CRISPR, which allows scientists to alter DNA sequences and modify gene function, has already shown promise in eliminating the genetic coding that drives the development of children’s cancer.
The team in Tuesday’s study used an enzyme, CRISPR-Cas13b, that binds to relevant RNA sequences on the novel coronavirus and degrades the genome it needs to replicate inside human cells.
Lead author Sharon Lewin from Australia’s Peter Doherty Institute for Infection and Immunity told AFP that the team had designed the CRISPR tool to recognize SARS-CoV-2, the virus responsible for COVID-19.
“Once the virus is recognized, the CRISPR enzyme is activated and chops up the virus,” she said.
“We targeted several parts of the virus – parts that are very stable and don’t change and parts that are highly changeable – and all worked very well in chopping up the virus.”
The technique also succeeded in stopping viral replication in samples of so-called “variants of concern” such as Alpha.
Although there are several COVID-19 vaccines already on the market, available treatment options are still relatively scarce and only partially effective.
‘Need better treatments’
Lewin said that using the CRISPR technique in widely available medicine was probably “years, not months” away.
But she insisted that the tool could still prove useful in tackling COVID-19.
“We still need better treatments for people who are hospitalized for COVID,” said Lewin.
“Our current choices here are limited and at best they reduce the risk of death by 30 percent.”
Lewin said the ideal treatment would be a simple antiviral, taken orally, that patients are given as soon as they test positive for COVID-19.
This would prevent them getting seriously ill, and in turn alleviate pressure on hospitals and care systems.
“This approach – test and treat – would only be feasible if we have a cheap, oral, and non-toxic antiviral. That’s what we hope to achieve one day with this gene scissors approach,” said Lewin.
Co-author Mohamed Fareh from the Peter MacCallum Cancer Centre said that another benefit of the research was its potential to be applied to other viral diseases.
“Unlike conventional anti-viral drugs, the power of this tool lies in its design-flexibility and adaptability, which make it a suitable drug against a multitude of pathogenic viruses including influenza, Ebola, and possibly HIV,” he said.
© Agence France-Presse