Oxford's oldest student newspaper

Independent since 1920

Paxlovid: How a new oral drug against COVID-19 was designed

Matthew Clark reports on a new Oxford University study.

Despite progress with vaccinations, the highly contagious Omicron variant has caused cases to surge. Along with other UK approved drugs such as Merck’s Molnupiravir, Pfizer’s oral treatment, Paxlovid, could be a useful tool for doctors to treat patients. This antiviral was highly successful in clinical trials: compared with a placebo, it reduced the risk of hospitalization or death from COVID-19 by 88% if given within 5 days of the onset of symptoms. But how does it actually work?

Viruses are famous for having incredibly compact genomes. This allows them to replicate quickly and squeeze into a tiny capsid. One technique they use to achieve this is to store most of their proteins inside one gene ‘reading frame’ with no space in between. The product of this gene is like a long string of sausages, and it must be cut up into pieces by an enzyme called a protease.

Paxlovid is a ‘competitive inhibitor’ of this protease. It binds to enzyme incredibly strongly and blocks off the active site from cutting up the polyprotein. The Coronavirus can no longer express any proteins and will not be able to replicate.

On 13th March 2020, a Pfizer researcher in Massachusetts USA called Dafydd Owen was sent home from work. But he didn’t have time to sit around binging Netflix. “We were all sent home on that Friday, and the world was completely different,” he says.

Over the weekend, Owen and his team laid out a plan to resurrect an old and forgotten molecule and re-engineer it to be an oral drug against COVID-19.

In 2003, researchers at Pfizer had discovered an antiviral compound that blocked the SARS-2002 coronavirus protease. Owen was tasked with designing a molecule that could be taken orally and efficiently absorbed into the bloodstream – without changing it too much that it could no longer inhibit the protease.

A key alteration to the 2003 compound was the formation of a hydrophobic ring that was strategically placed to cover up a super hydrophilic area. “Making rings is kind of boom or bust in medicinal chemistry.” Owen says. “You either win big or you lose big.”

Another important change was the addition of fluorine atoms. This makes a molecule more ‘lipophilic’ and able to cross the cell membrane more quickly. This strategy has proven so successful that over 20% of pharmaceuticals are now fluorine based.

On September 1st 2020, Dafydd’s team received the results of their study in rats and it proved the nirmatrelvir drug could be administered orally, and still act as an effective protease inhibitor.

A phase 1 clinical trial on humans began in February 2021, a remarkably speedy outcome for a process that usually takes a decade.

“We need to show that antivirals still have real benefits for these people,” said Eddie Gray, chair of the UK government’s antivirals taskforce.

This data will be provided by an Oxford University study, called Panoramic, which is assessing the impact of antivirals on vulnerable but vaccinated people in the UK.

Image: Matthew Clark

Check out our other content

Most Popular Articles