Drug discovery: Crystal structure reveals interactions between the drug target of SARS-CoV-2 and its inhibitor

The molecular interactions between carmofur, a chemotherapy drug identified as a promising compound to develop treatments for COVID-19, and SARS-CoV-2 are described in a crystal structure paper published in Nature Structural & Molecular Biology. The findings could provide the basis for the design of carmofur derivatives that could be more potent in their action on SARS-CoV-2.

Researchers are searching for drugs that can prevent the SARS-CoV-2 virus from replicating, which would halt the progression of infection in patients. The SARS-CoV-2 main protease (Mpro), an enzyme involved in viral replication, has been identified as a potential target for this kind of treatment. Haitao Yang and colleagues previously identified carmofur, an approved drug that has been used to treat colorectal cancer since the 1980s and has shown clinical benefits in treating breast, gastric and bladder cancers, as one compound that can inhibit Mpro in laboratory experiments. However, the molecular details of how carmofur inhibits Mpro are unknown.

In this paper, the authors present the X-ray crystal structure of SARS-CoV-2 Mpro bound to carmofur. The structure reveals that the drug directly modifies the catalytic Cys145 element of SARS-CoV-2 Mpro. This, and further details of how the drug interacts with Mpro that are elucidated by the structure, could provide the basis for the design of more potent derivatives of carmofur. Additionally, the authors conclude that, since Mpro is a sequence that remains conserved across all coronaviruses, carmofur—and drugs developed from it—may be effective against a broad spectrum of coronavirus infections.