If you walked into a car factory with a sheaf of blueprints and told the manager that she had to switch to making motorcycles, she would call security.
If, however, you had hypnotic powers of persuasion or the Force was strong within you, you could get the factory to retool and make all the necessary parts, but then you would have to train the workers how to assemble the motorcycle parts in the right order. Amazingly, a virus that has taken over your cell and made it produce virus parts does not have to do this: the parts assemble themselves.
Let me say that again: the virus parts assemble themselves. Ikea furniture with no work involved.
This is one of the most remarkable things about molecules and one of their properties that really highlights how limited our intuition is when it comes to the atomic world.
In my last column, I discussed vaccines and drugs and how they work to inactivate viruses. Today, I am going to describe some of the steps in viral assembly and how they provide further opportunities for developing a cure - one that does not involve your immune system.
Your cells are a bit like a factory but instead of a car factory they are factories that produce everything from rubber bands to nuclear submarines. In other words, the variety of things they make is enormous and each of those things is important for keeping you alive.
When a coronavirus takes over your cell by introducing its RNA genome, it provides the instructions for making viral parts, parts that your cell would not normally make. The coronavirus needs about 30 proteins to assemble new viruses. Some of these proteins hijack your cell’s machinery, preventing it from carrying out its normal functions and instead forcing it to work on assembling new viruses. Others do the virus-specific task of copying viral RNA into more RNAs, something that your cells never do. Yet others make molecular scissors - called proteases - that chop up the viral proteins into smaller parts that each have their own function.
Now comes the amazing part: all the things that become new virus particles - the RNA genome, the spike protein, the lipid membrane, the protein hooks that latch onto your cells - all of these parts come together by themselves and make new viruses.
Think about it. If you took all the parts for a skateboard, put them in a box, and shook, you would never end up with a skateboard. Even if you used magnets and velcro to make certain bits stick together, there would be no way to ensure they came together in the right order.
The molecules in your cells, however, whether they are your own or imposters from a virus, are so tiny that the heat in the environment jostles them around madly. In addition, they have just the right sticky bits, hooks, latches, complimentary shapes, and so on to make them come together and stay that way.
They also fix themselves as they assemble because each new part that adds on to the assembling virus makes the previous parts more stable. If the previous parts came together incorrectly, then after a few seconds they would fall apart again, as the next piece can’t join them. Only the properly-assembled ones get stabilized by the next part adding on.
So how does this help with finding a cure? I mentioned previously that the viral machine that copies RNA into RNA - the so-called RNA-dependent RNA polymerase - is a good target for medicines, because your cells never do that. Only their viral invaders do. So a chemical that prevented the RNA copying from happening, by getting into the polymerase and jamming it, would potentially be a good drug.
Another great target is the molecular scissors I mentioned. Unlike your own proteins, which are made one at a time and the right size and shape to do their jobs right out of the box, coronavirus proteins are made in one long string. It’s very much like the little bag of important screws and hex wrenches that comes with Ikea furniture. You have to cut the bag off the furniture and then cut it open to take out the parts you need. Similarly, the viral parts are all stuck together and one of the first items on the string is the scissors that cut all the proteins apart.
Unlike the spike proteins of viruses, which change frequently and are highly variable from one virus to another, the viral proteases (molecular scissors) are highly conserved. That is why some of the best anti-HIV drugs are protease inhibitors: they stop the viral proteases from working, and the virus can’t mutate to become resistant because the molecular scissors would no longer work.
These proteases are therefore important targets for the companies and research labs that are currently looking for a cure for COVID-19. Presumably there are some candidate drugs that are similar to the ones used for HIV, but frustratingly it could still take months to test them and make sure they are safe.
-Stephen Rader is a professor of biochemistry at the University of Northern British Columbia. His laboratory studies how RNA is processed by our cells and he is the founder of the Western Canada RNA Conference.
