A new way to take down SARS-CoV-2

Scientists report a small molecule that can stop SARS-CoV-2—the virus that causes COVID-19—from replicating in cells and in mice by blocking an enzyme that hasn’t received much attention in antiviral efforts. The strategy could lead to treatments for coronaviruses beyond SARS-CoV-2 as well as other RNA viruses, including those causing Ebola and dengue.

The compound, known as TDI-015051, interferes with the viral methyltransferase enzyme NSP14. NSP14 adds methyl caps to the virus’s messenger RNA, allowing the virus to evade detection by a host’s immune system. There’s no protein in humans that’s akin to NSP14, which makes it a good drug target. And the enzyme is similar in many coronaviruses, which suggests that TDI-015051 could be a pancoronavirus antiviral. Nirmatrelvir, the key component of the COVID-19 antiviral Paxlovid, goes after a different enzyme entirely, the virus’s main protease. The researchers suggest that antiviral combinations that target both enzymes could help sidestep resistance the viruses are known to develop to antiviral drugs.

NSP14 “is absolutely essential for viral replication in many viruses but has just not been touched for drug discovery,” says Thomas Tuschl, an expert in RNA at the Rockefeller University who led the project that identified TDI-015051. He suspects that drugmakers have been deterred by the challenge of making RNA analogs and setting up high-throughput screening for inhibitors of the enzyme—something that his lab was well positioned to do.

Tuschl and coworkers screened 430,376 unique compound to identify inhibitors of NSP14. From the handful of hits they got out of that screen, they started a medicinal chemistry campaign. Tuschl says it took 13 chemists working on the program full-time for a year to make the molecules that led them to TDI-015051.

A crystal structure of the compound bound to NSP14 shows that TDI-015051 occupies the enzyme’s guanine cap-binding pocket, adjacent to S-adenosylhomocysteine, which is a molecule involved in the methyl transfer process.

In tests with cells and mice infected with SARS-CoV-2, TDI-015051 prevented the virus from replicating. It also stopped SARS-CoV-1 replication in cells—suggesting its use as a pancoronavirus antiviral (Nature 2024, DOI: 10.1038/s41586-024-08320-0).

Jia Zhou, who studies drug discovery at the University of Texas Medical Branch and was not involved in the research, calls TDI-015051 an intriguing discovery. “The remarkable in vitro and in vivo findings provide the proof-of-concept results to support a novel antiviral strategy by targeting the viral cap methylases,” he says in an email. Although TDI-015051 has a drug-like structure, Zhou says its pharmacological properties, such as its short half-life and high clearance, don’t make it a great drug candidate, but he says that it’s a good starting point.

To that end, Tuschl says the researchers are looking to partner with a pharmaceutical company to develop the compound into a drug.