A pill for the pandemic
From the moment scientists first identified the novel coronavirus, they rallied to combat the disease, creating highly effective vaccines at an unprecedented pace.
However, not everyone can or will be vaccinated, and efforts to repurpose existing medicines – which were not designed with coronaviruses in mind – can yield limited results. There remains a critical need for antivirals that can slow or stop the course of coronavirus infections, especially as variants continue to emerge.
So even as vaccines are distributed globally, work on antivirals continues to accelerate. Researchers around the world, including at Novartis, are tackling the challenge by openly sharing knowledge and resources, and establishing new frameworks for collaboration. In this spirit, scientists across academia and industry have convened to discuss the latest research and strategies at virtual forums, including the inaugural Science of Therapeutics Symposium, hosted by the Novartis Institutes for BioMedical Research (NIBR).
Because antivirals stop viruses from replicating, they are most effective in the early stages of an infection. This means that, optimally, such drugs should be widely available and easily taken by anyone infected with the virus.
“The ideal antiviral against coronaviruses should be in pill form, so that people can take something at home to stop the virus as soon as they feel symptoms, test positive or even think that they’ve been exposed,” says Julien Papillon, a medicinal chemist at Novartis.
The coronavirus copy machine
To this end, Novartis scientists are going after key machinery that makes the virus so dangerous.
At a basic level, the coronavirus is a delivery package for its genome – a genetic blueprint for making more coronaviruses. Once inside a cell, the first thing this blueprint does is trick the cell into creating a molecular copy machine for the virus.
This machine has one task: make copies of the virus’s genome. Each new copy tells the cell to build more copy machines, which then spew out even more viral blueprints.
This cycle quickly overwhelms the cell, ultimately transforming it into a dedicated coronavirus production factory. Soon, newly minted coronaviruses flood out of the cell to infect its neighbors and eventually other people.
But the copy machine has weaknesses.
It is complex and is made of many different proteins. These components are stuck together when first created – similar to how the parts of a toy model are held in a plastic frame when first taken out of the box. To free the parts and assemble the machine, the virus uses a pair of protein scissors, called Mpro (or main protease).
In a collaboration with colleagues at the University of California, Berkeley, in the US, a Novartis team set out to identify molecules that can essentially weld these scissors shut, preventing the copy machine from ever being assembled.
Without the copy machine, the virus can’t multiply and cause harm.
Preparing for the next pandemic
The Novartis team has spent the past year studying such molecules, which must be put through their paces in the lab before starting clinical testing. Having narrowed down the possible candidates, it is moving forward, supported by a grant from the Bill & Melinda Gates Foundation. Groups around the world are engaged in similar efforts to neutralize the coronavirus by disabling Mpro, copy machine components or other targets.
It will take time to test potential treatments in patients. But medicines that specifically stop Mpro could offer intriguing benefits that would extend beyond the COVID-19 pandemic.