New screening method identifies COVID-19 protein inhibitor

A team at the Baylor College of Medicine, US, have used an innovative, fast and cost-effective drug discovery technology to screen billions of compounds for a potential treatment against viruses. Using this method, they were able to identify an inhibitor of a viral protein that is needed for propagation of viruses, specifically the COVID-19 virus SARS-CoV-2, called M^pro.

The more commonly used method for discovering drugs is high throughput screening (HTS), which involves screening at most a million compounds in individual test tubes which can be slow and expensive. The researchers instead used a method called DNA-encoded chemistry technology, which enabled them to screen four billion DNA-encoded molecules all in one test tube against a key SARS-CoV-2 protein to find a molecule that may modify how that protein behaves.

“It is a process that allows us to test over 1,000 times more compounds than the traditional process and at a much faster pace. We applied it to finding molecules that hit the viral protein M^pro,” explained co-contributing author Dr Damian Young.

The method that the team used to screen their compounds is not entirely new and has been mostly applied to treating different forms of cancer. However, this is the first time that it has been reported to be effectively applied to COVID-19.

“The DNA-encoded chemistry technology process involves a simultaneous screen of billions of molecules in which each drug-like molecule is tagged with a DNA barcode,” said Dr Martin Matzuk, a co-contributing author. “The molecules that ‘stick’ to the protein are identified by sequencing of their attached DNA ‘barcode.’ This is a rapid drug discovery screen, and our study demonstrates the enormous potential to find unique molecules that can inhibit viruses and help in this and in future pandemics.”

The method identified M^pro , the SARS-CoV-2 main protease that is a key component for the lifecycle of coronaviruses and a therapeutic target that is independent of the current vaccine strategies. “By blocking M^pro with small molecules, we are blocking SARS-CoV-2 from replicating in cells. These studies are highly encouraging and indicate that this process could be used in the future for emerging viruses, including other coronaviruses,” commented co-first author Dr Srinivas Chamakuri.

The next steps to further test the inhibitor against M^pro against COVID-19 will involve animal models and other lab safety tests before it can begin human trials.

The findings were published in PNAS.