X-ray screening finds two drugs that could help treat COVID-19

Researchers have screened nearly 6,000 drug molecules and found inhibitors of the main protease of SARS-CoV-2, the virus that causes COVID-19 (Science 2021, DOI: 10.1126/science.abf7945). Two lead compounds are being assessed to see if they could treat people with COVID-19.

The team, led by Alke Meents at the German Electron Synchrotron (DESY), looked for compounds that target the main protease( Mpro) an essential part of the virus’s replication process. That important role has made it a target for drug designers since the beginning of the pandemic. Mpro is also the target of an oral antiviraldescribed by Pfizer researchers during the American Chemical Society Spring 2021 meeting (see page 7).

In the new work, researchers mixed compounds from two libraries of drugs and combined each one with copies of the viral protease Mpro at physiological pH. The researchers then co-crystallized the enzymes and drugs. They used X-ray crystallography to get atomic-level images of the 43 drugs that bound the enzyme, and these images told the researchers where and how the drugs bind Mpro. Some drugs bind the enzyme’s active site, which the enzyme uses to snip free viral proteins in an infected cell; others bind allosteric sites, binding these sites can affect the enzyme’s ability to function without the drug getting all the way into the enzyme’s active site.

The researchers then tested how well the drugs they identified fight the virus in infected cells. Two—calpeptin and pelitinib—worked well enough that they are being investigated further. Calpeptin binds the active site, and pelitinib binds to an allosteric site.