Drugs that target human proteins could stop viruses from hijacking cellular machinery.Credit: Michal Bednarek/PHOTOCREO/Shutterstock
Like many scientists over the last year, Nevan Krogan has turned his attention to the SARS-CoV-2 coronavirus. But Krogan, a molecular biologist at the University of California San Francisco, has taken a different approach than most. Instead of analysing the virus, he is investigating how human proteins respond to it.
The task was daunting. “We knew nothing about this virus,” he says. But by analysing human proteins used by the virus to replicate, Krogan has identified several existing drugs known to target these proteins, and is testing them further. "We’re excited about several potential treatments for COVID-19," he says.
Krogan’s team first found a way to insert each of the 29 proteins made by the SARS-CoV-2 virus into human cells in the lab. They started with a human kidney cell line. With a technique called transfection, they used chemical reagents to smuggle viral genetic material inside the cells. The kidney cells then express the different viral proteins, and the researchers identified which human proteins bound to these viral products.
The kidney cell line is a lab staple, and easy to use in these experiments. But because SARS-CoV-2 targets the lungs, it’s important to conduct the same tests in primary lung cells. Such cells, drawn directly from the human body, are difficult to transfect. So Krogan’s group instead used lentiviruses produced by GenScript, a life science company based in Piscataway, New Jersey, as a delivery vector to transduce and insert the viral material into the target lung cells.
These lung cell studies are ongoing, but the kidney cell line studies have already produced more than 300 mapped interactions between SARS-CoV-2 proteins and human proteins. This ‘interactome’ forms the starting point for the next part of the project: repurposing existing drugs as a potential treatment for COVID-19.1
Defeating viral defenses
Krogan’s collaborators have identified almost 70 drug candidates that interact with these proteins. Groups around the world have tested whether these potential drugs could limit SARS-CoV-2 infection in lab conditions.
Krogan has focused especially on a multiple myeloma treatment, plitidepsin, that targets a protein called eEF1A that initiates protein biosynthesis. Initial tests in a mouse model of COVID-19 were promising and worth further study, the researchers reported in Science.2 Since then, plitidepsin has been approved for phase 3 clinical trials on COVID-19 in 12 countries.
To go from an unknown virus to clinical trials within a year is unprecedented, says Krogan. The speed is possible because repurposing existing drugs streamlines the drug approval process. But Krogan had also spent years fostering fruitful collaborations prior to this project. “You don't just pick up a phone and say, ‘Let's all work together,’” he points out.
Other scientists see value in targeting human proteins in this way. “It’s a really smart strategy to overcome the big problem that we have had in fighting viruses,” says molecular biologist Rocco Savino of the University of Catanzaro.
“Our proteins can’t mutate as fast as viral proteins do,” he says. “So this is a way to develop drugs that may maintain their effect even against new mutations of the virus.”