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Covid-19 pandemic: how modelling can support drug development

Central to the fight against Covid-19 is the clinical development of drugs, including novel compounds and those already approved for other indications. One way to support these efforts is through computational models, which can support better understanding of possible drug targets, as well as improve patient monitoring in trials.

The first of the National Institute of Allergy and Infectious Diseases’ (NIAID) Covid-19 research priorities is to improve understanding of the disease and the novel coronavirus that causes it, SARS-CoV-2. This helps with understanding the transmission of the disease, including determining whether it is likely to be seasonally circulating, as well as why Covid-19 so dramatically affects some individuals, while others remain asymptomatic.

But better knowledge about the virus and the disease can also support the identification of new drug targets or which existing drugs could help tackle this viral disease. Drugs are essential to stopping more suffering at the hands of Covid-19; at the time of writing, more than 206,000 people have tragically died from the disease globally, according to GlobalData’s coronavirus dashboard.

All viruses have different structures that impact how they infect and enter people’s cells and then reproduce. Coronaviruses use a so-called ‘spike protein’ as one method to invade patients’ cells – this is where they get their name, as ‘corona’ means crown in Latin – however, each virus in that class has a slightly different-shaped protein.

In mid-March, National Institutes of Health (NIH)-funded scientists at the University of Texas at Austin mapped the molecular structure of the SARS-CoV-2 spike protein using cryo-electron microscopy with the aim of supporting both vaccine and drug development. They found it was similar to the SARS-CoV virus, which was responsible for the 2003 SARS outbreak; researchers in China had already shown both SARS-CoV and SARS-CoV-2’s spike proteins attached the same receptor, ACE-2, to invade patient’s cells.


3D modelling of the Covid-19 spike protein

Knowing the 3D structure of the interaction between ACE-2 and the spike protein means “we can make highly accurate predictions as to which molecular shapes can fit into pockets of that interaction to disrupt it or prevent it completely”, notes ImmunityBio chief scientific officer Shahrooz Rabizadeh, therefore “we may either find that currently approved drug molecules could work to fight Covid-19 infection, or novel drug candidates would be made.”

“Once a therapy targeting the spike protein is developed, it will block viral entry into a human cell, which would stop or substantially slow down further spread of the virus to other cells and make the disease progression much milder and easier to treat,” Rabizadeh explains. “In addition, any damage to the lung tissue would be far less severe.”

A 3D model of the protein could also support vaccine development.

“The spike protein may act as an antigen forming the basis of a vaccine: isolated spike protein or its fragments administered to a healthy person would not cause infection, but rather would promote the body’s development of specific antibodies against SARS-CoV-2,” says Rabizadeh.


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