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Asthma drugs show the way to drugs to prevent and treat Covid-19: Nsp1, a new target

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To survive and replicate inside our cells, a virus must be able to adapt them to its advantage. This means altering the metabolism, physiology and gene expression of cells. Often these adaptations are part of a strategy to circumvent and thwart our innate immune system – a virus can’t get very far if our immune system can recognize it early on. Thus, suppressing our immune response is one of the top priorities of a virus. SARS-CoV-2 is particularly astute in this regard, possessing many different tactics that help keep it under the radar. But there is a downside to this ruse, it is very complex. A lot of different processes and things have to come together to make it work. Block one, and everything can fall apart. This makes it an excellent avenue of therapeutic intervention. A group of researchers based at the Indian Institute of Science (IISc) has discovered a new target: the non-structural protein 1 (NSP1) of SARS-CoV-2. Posted in eLifetheir work shows that binding and blocking NSP1 results in decreased viral replication in human immune cells.

There are two broad categories of viral proteins: structural and non-structural. Structural proteins are the components of the virus particle itself. They provide the building blocks the virus needs to spread from person to person. Non-structural proteins, on the other hand, are not a component of the virion particle itself. Instead, they are produced by the virus once inside host cells. Here, nonstructural proteins aid in viral replication by regulating transcription and altering host defenses.

NSP1 is a particularly versatile non-structural protein, with a variety of different functions related to both immunosuppression and viral replication. It is one of the first viral proteins released once inside the cell. The main function of NSP1 is to inhibit the translation of host messenger RNA (mRNA). To replicate, viruses must delete genes from the host cell and instead promote their own synthesis. NSP1 helps by binding to ribosomes, which act as the “cellular machinery” by which proteins are made. Specifically, NSP1 is composed of two sections, an N terminal and a C terminal. It is the C terminal that binds deep into the small ribosomal subunit (40S) mRNA inlet tunnel. Once bound, NSP1 prevents translation of host messenger mRNA, but in an act of tricky trickery, still allows translation of viral mRNA (Figures 1 and 2).

Downstream, sabotage of host mRNA translation means that a variety of important antiviral proteins are not produced. This weakens the immune response our bodies can muster, and in a dangerous feedback loop, it’s even easier for the virus to replicate and spread unchallenged.

In addition to its central role in viral replication and host immunosuppression, Asafar et al. focused on NSP1 as it is one of the SARS-CoV-2 proteins with the lowest mutation frequency. That is to say, it changes very little over time and from variant to variant. Any drug that wants to remain effective against SARS-CoV-2 must contend with the rise of new variants – focusing on a highly conserved and functionally important protein like NSP1 improves the odds.

Once they had chosen their target, the team of scientists combed through a database of approximately 1,600 FDA-approved drugs. Turning to computer modeling, they isolated drugs that might bind to the C-terminal NSP1. On a final list of ten candidates, Asfar et al. reduced to one, montelukast.

Montelukast is generally used to treat asthma and hay fever. How might this work to curb SARS-CoV-2 infection? In a nutshell, by binding to the C terminal of NSP1 before NSP1 has a chance to bind to our ribosomes. This obstructs the binding site of NSP1 and prevents it from inhibiting the translation of mRNA from our cells.

At least, that’s how it should work in theory. To find out if it worked in practice, the researchers engineered human kidney cells that express NSP1. They observed a notable decrease in mRNA translation and protein synthesis. Next, Asafar et al. exposed these cells to montelukast. The drug restored protein synthesis to normal levels, successfully counteracting the effects of NSP1.

Asafar and his colleagues also exposed human cells to the live SARS-CoV-2 virus and then treated those cells with montelukast. They witnessed a significant drop in SARS-CoV-2 spike protein expression, suggesting reduced viral replication. The results indicate that montelukast successfully prevented NSP1-mediated inhibition of host mRNA translation, allowing normal production of antiviral proteins and reduced capacity for viral replication (Figure 3).

Despite the positive results, the strength with which montelukast binds to NSP1 – known as “binding affinity” – is still relatively low. Asafar et al. admit that montelukast alone probably won’t be up to the task. But its mechanism of action, the way it prevents SARS-CoV-2 NSP1 from inhibiting host mRNA translation, is viable and provides a good starting point for future drug design. Above all, it hints at an overall strategy for successful therapeutic intervention: isolating the specific processes by which SARS-CoV-2 manages to suppress and evade our immune response and discovering drugs that inhibit each. The book, Natural immunity and Covid-19: what it is and how it can save your life, provides a detailed overview of these processes. Figure 4 highlights the multiple points of sensitivity of the virus. I foresee a day when there will be at least twenty different classes of drugs (with multiple drugs in each class) each targeting a different viral protein. When used in combination, these drugs will be safe and effective in preventing and treating Covid-19, whatever variant may arise.