Small molecule takes aim at the RNA of SARS-CoV-2

Scientists have identified a potential target for therapeutics against SARS-CoV-2, the virus that causes COVID-19. The discovery hinges on a small molecule that latches onto and inhibits a structure in the SARS-CoV-2 RNA genome, preventing the virus from pumping out the proteins it uses to replicate and infect cells (ACS Cent. Sci. 2020, DOI: 10.1021/acscentsci.0c00984). Although it may take years before any therapeutic could be developed from the proof-of-concept work, the approach could be helpful in battling coronaviruses in the future.

In general, drug discovery and development efforts have largely focused on proteins, says Milka Kostic, a chemical and structural biologist at Dana Farber Cancer Institute, who was not involved with this study. Scientists know less about RNA’s structure and how to target it, they add. But “there could be advantages to intercepting RNA” instead of going after the proteins made from it, Kostic says. Past efforts at targeting the RNA of viruses have taken a similar approach to bind the RNA of hepatitis C and ongoing work is exploring HIV as another RNA target.

Matthew D. Disney, a chemical biologist at the Scripps Research Institute, and his team screened thousands of molecules and tested how well a handful of these compounds bound to a fold of viral RNA that is unique to SARS-CoV-2. The virus depends on this hairpin to control the translation of certain key proteins. Using cells into which that bit of RNA had been introduced, the researchers found that one molecule, a quinazolinamine, stuck to the structure and gummed up the works, reducing expression of a gene it controls by about 25%. “It’s an extremely high-affinity, drug-like small molecule,” Disney says. “That was a little surprising to me.”

The work is a “great beginning,” says Maria Duca, a medicinal chemist at the University of Côte d’Azur, who was not involved with the study. People sometimes doubt whether small molecule drugs can selectively target RNA because RNA is very negatively charged, dynamic and can bind to many small molecules, she explains. But this work demonstrates that “it is possible, actually, to be very specific for a particular target.”

The researchers then attached the RNA-targeting quinazolinamine to another compound that recruits RNA-degrading enzymes—“little RNA garbage disposals, which come in and chew up that RNA,” says Amanda L. Garner, a chemical biologist at the University of Michigan who was not involved with the study. Called a RIBOTAC, or ribonuclease-targeting chimera, this combination kicked off the destruction of the SARS-CoV-2 RNA in cells, the researchers found. While these first studies are a proof a concept, being able to “completely destroy the virus, just by having a simple small molecule bind to that virus would be really exciting,” Garner says.

Much more work is needed to evaluate the RNA-binding molecule’s therapeutic potential, Disney says. That includes studying the compound with infectious virus and in animal models. And for COVID-19, Garner says, “it will certainly not be ready within the timeframe to address our very urgent need. But … we’re going to be hit with other RNA viruses in the future,” she adds, so setting a framework for how to efficiently develop therapeutics to drug these viruses “would be incredibly impactful.”

To that end, Disney’s team is also exploring whether other RNA structures that may be shared among different coronaviruses could be exploited as potential drug targets. “In principle you can use the pipeline that’s laid here,” Disney says.