The latest piece of COVID-19 information circulating in my Division Monday was a pre-print of a manuscript submitted to Nature (perhaps the world’s most highly regarded scientific journal) regarding the results of a molecular tour de force investigation of COVID-19’s protein components and the human proteins with which they interact, examining properties of existing drugs which might disturb those interactions and thereby cripple the virus. The paper has not finished going through the peer-review process, so the final “official” report could end up looking slightly different.
There are 95 authors listed in the masthead, almost all with various UCSF associations, but Paris, Seattle and New York City are also represented.
They started by taking the virus apart. That 30,000 base pair RNA genome has 14 ”open reading frames” you could call genes which direct synthesis of 14 globs of protein which manage to self digest and reassemble themselves into 16 non-structural proteins (which direct the virus’ dirty work on the cell), 4 structural proteins (which the virus presents to the world in its “crown”) and 9 “accessory factors” which have a mysterious role. They managed to clone all 29 of these into plasmids (DNA taken up by cells and expressed) and gotten cultured human cells to crank out good amounts of each one. They could verify each product was the real deal in 27 instances. Then they mixed them up with proteins from human cells from 16 different organs coronavirus is known to infect. The identified 332 interactions between different virus proteins and different cell materials. Here is where the rubber was meeting the road when coronavirus sets up shop. Interfere with those interactions and maybe you’ve got a chance. To be more sure that the human proteins interacting in the test tube were relevant, they checked the evolutionary profiles of the proteins, judging that proteins more stable across evolution would more likely be real viral targets. The 332 looked like they filled this bill. They characterized the nature of the various interactions, finding interactions related to lipid modifications and vesicle trafficking (the virus moves in and out of intracellular vesicles and appropriates the cell’s lipids for its own coat), interactions with multiple innate immune pathways (the defenses our cells have at the ready regardless of identity of invader), interactions with a Cullin ubiquitin ligase complex (don’t ask me), and interaction with bromodomain proteins (important in regulating gene transcription).
Then came the “wow” part (if the molecular virology thusfar didn’t tickle you as much as it did this old virologist). They sought to find molecules that would target human proteins in the SARS-CoV-2 “interactome” (a term I think they just coined, but a nice way to describe whatever two-backed beast that formed whenever bits of corona and human came together). Drugs are no longer some sort of mystery potion drawn from the doctor’s bag. Molecular structures are known, and at least putative mechanisms exist. And they’re all catalogued. Chemoinformatics, they call it. They found 62 drugs that could conceivably modulate the virus-human interactions they’d characterized. Some are still pre-clinical. But some old war horses showed up, including Depekote (valproic acid), an anti-seizure drug, Haldol (haloperidol), an anti-psychotic (which we might all need if this goes on much longer), chloroquine (Aralen) of course, CellCept (mycophenolic acid, an immune suppressant and anti-transplant drug), ribavirin (already in the Chinese guideline), and even metformin (a common diabetes drug). As I type this, I plan to make you a full table, which the 95 authors did not. I’m going to save that for a later post so I can get this out. There’s not a lot of room in Nature. Not a problem here, but I have your attention span to consider.
Please don’t go asking your doctor for any of these drugs. That’s happening badly enough with Plaquenil already. But realize this sort of high-tech investigation is going on and could rapidly lead to new treatments for our current plague. Trust that the nerds have their noses to the grindstone and good stuff is bound to turn up.
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