A mildly insane idea for disabling the coronavirus

Colorful blobs cluster together like a bunch of grapes.
Enlarge / Diagram of the structure of the virus’ spike protein.

When the COVID-19 pandemic was first recognized for the threat that it is, researchers scrambled to find anything that might block the virus’ spread. While vaccines have grabbed much of the attention lately, there was also the hope that we could develop a therapy that would block the worst effects of the virus. Most of these have been extremely practical: identify enzymes that are essential for the virus to replicate, and test drugs that block similar enzymes from other viruses. These drugs are designed to be relatively easy to store and administer and, in some cases, have already been tested for safety in humans, making them reasonable choices for getting something ready for use quickly.

But the tools we’ve developed in biotechnology allow us to do some far less practical things, and a paper released today describes how they can be put to use to inactivate SARS-CoV-2. This is in no way a route to a practical therapy, but it does provide a fantastic window into what we can accomplish by manipulating biology.

Throw it in the trash

The whole effort described in the new paper is focused on a simple idea: if you figure out how to wreck one of the virus’ key proteins, it won’t be able to infect anything. And, conveniently, our cells have a system for destroying proteins, since that’s often a useful thing to do. In some cases, the proteins that are destroyed are damaged; in others, the proteins are made and destroyed at elevated paces to allow the cell to respond to changing conditions rapidly. In a few cases, changes in the environment or the activation of signaling pathways can trigger widespread protein destruction, allowing the cell to quickly alter its behavior.

This system relies on a small protein called “ubiquitin.” When a protein is to be targeted for destruction, enzymes called ubiquitin ligases chemically link a chain of ubiquitins to it. These serve as a tag that is recognized by enzymes that digest any proteins with ubiquitin attached to them.

So, the idea behind the new work is to identify a key viral protein, and figure out how to attach ubiquitin to it. The cell would then take care of the rest, digesting the viral protein and thus blocking the production of any useful viruses in that cell. In this case, the researchers decided to target the spike protein that sits on the surface of coronaviruses and allows them to attach to and infect new cells.

Unfortunately, there are no proteins that attach ubiquitin to the viral spike protein. Or, rather, there were no proteins that fit that description.

But a team at Harvard has now produced one.

Bioengineering

The team’s method of doing so started with the fact that we do know something that sticks to the viral spike protein: the cellular protein it latches on to in order to enter the cell. This is called the angiotensin-converting enzyme 2,

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