Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.
In March 2020, as the scope of the COVID-19 pandemic was coming into view, Jen Nwankwo and colleagues turned a pair of artificial intelligence (AI) tools against SARS-CoV-2. One newly developed AI program, called SUEDE, digitally screens all known druglike compounds for likely activity against biomolecules thought to be involved in disease. The other, BAGEL, predicts how to build inhibitors to known targets. The two programs searched for compounds able to block human enzymes that play essential roles in enabling the virus to infect our cells.
While SUEDE sifted through 14 billion compounds in just hours and spit out a hit, BAGEL made equally fast work of designing a lead. Nwankwo, CEO of a Massachusetts biotech startup called 1910 Genetics, asked a chemical company partner to synthesize the compounds. A week or so later, her team received the orders, added each compound in turn to human cells, and learned that each blocked its target and prevented viral entry into cells. 1910 Genetics is now looking to partner with antiviral drug developers to pursue animal and human trials. “It shows that AI can massively accelerate drug design,” Nwankwo says.
Designing and developing a medicine is almost always painfully slow, regularly taking at least a decade. Many steps—such as animal studies, tweaking molecules to avoid side effects, and clinical trials—can’t be accelerated. But the race toward new treatments against COVID-19 is off to a blistering start as researchers accelerate other parts of the search, deploying supercomputers, robots, synchrotrons, and every other tool they have to find and lab test possible medicines at speed. According to a biotech industry drug tracker, some 239 antiviral molecules against COVID-19 are under development, targeting multiple parts of the viral life cycle.
Antivirals have proved critical in fighting other infections such as HIV and hepatitis C. Such drugs will be vital in the struggle against the pandemic coronavirus, too, despite the ongoing rollout of COVID-19 vaccines. “We know not everyone will be able to take the vaccine or respond to it,” says Mark Denison, a virologist at Vanderbilt University. Vaccines may also lose effectiveness as immune protection wanes or viral variants emerge. “So, continuing development of antivirals is critical,” Denison says.
To date, most of that search has centered on “repurposed” compounds, antivirals originally developed to combat other diseases. (Other repurposed drugs, such as the steroid dexamethasone, target the body’s reaction to infection rather than the virus itself.) “Drug repurposing made sense as the first thing to try,” Nwankwo says. Many repurposed antivirals have shown promise against SARS-CoV-2 in cell and animal studies and are now in clinical trials. One, remdesivir, has already proved to speed recovery by a few days in very ill people. But several other repurposed antivirals have failed to prove effective.
We know not everyone will be able to take the vaccine or respond to it. So, continuing development of antivirals is critical.
As a result, says Francis Collins, director of the National Institutes of Health (NIH), “We really, really need a bunch more [antivirals].” Buoyed by almost daily advances in understanding SARS-CoV-2, the rapidly growing list of new compounds that might block it, and ongoing clinical trials—some of them late stage—Denison and others hope to deliver effective drugs this year. Says Andrew Mesecar, a structural biologist from Purdue University: “I am confident we will have more treatments for coronavirus.”
As viruses go, SARS-CoV-2 is a behemoth, with some 30,000 letters of RNA in its genetic code. Those letters encode 29 viral proteins that enable the virus to infect cells, reproduce, escape, and spread. “We’re fortunate this virus has provided us with so many targets, so many opportunities for intervention,” says Sandra Weller, a molecular biologist at UConn Health.
The 29 proteins come in three main categories: structural proteins that make up the outer coat; nonstructural proteins (NSPs), most of which help the virus replicate; and accessory proteins, several of which appear to subdue the host’s immune response. Thus far, drug hunters have taken aim mainly at the structural and replication proteins, concentrating on molecules similar to those that have paid off in fighting other viruses.
SARS-CoV-2 has just four structural proteins. The envelope and membrane proteins make up the virus’ spherical shell, and the nucleocapsid protein shields its genome. The fourth protein, spike, protrudes from the shell, creating the crown of thorns that gives the virus its name and enables it to bind to angiotensin-converting enzyme 2 (ACE2) receptors, its main entry point into cells.