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But simply attaching its spike protein to a receptor is not enough for SARS-CoV-2 to gain entry into a cell. In fact, the spike protein is not active until it is cut in two. The virus takes advantage of another human enzyme—such as furin or the inelegantly named TMPRSS2—which can unwittingly come along and activate the spike protein. Several candidate drugs are meant to prevent these enzymes from unknowingly doing the virus’s work. One possible mechanism for the much-hyped hydroxychloroquine, the malaria drug Trump is fixated on, may be inhibiting this spike-activation process.
Once the spike protein is activated, SARS-CoV-2 fuses itself with the membrane of the host cell. It injects its genome, and it’s in.
Stop the virus from replicating
To a human cell, a naked SARS-CoV-2 genome looks like a specific type of RNA, a molecule that normally functions as instructions for making new proteins. So like a soldier who has gotten new orders, the human cell dutifully begins churning out viral proteins to make more viruses.
Replication is a relatively complicated step, which makes it a ripe target for antivirals. “There’s many, many proteins involved … there’s many potential targets,” says Melanie Ott, a virologist at the Gladstone Institutes and UCSF. For example, remdesivir, an experimental antiviral that is in clinical trials for COVID-19, targets the viral protein that copies the RNA, so the genome-copying step goes awry. Other viral proteins called proteases are necessary to free individual viral proteins that are linked together in one long strand, so they can go off and help the virus replicate as well. And still other proteins might help remodel the internal membranes of the human cell, creating bubbles of membrane that get turned into little virus factories. “The replication machinery sits on these membranes, and then it just starts making tons of viral RNA over and over and over again,” Matthew Frieman, a virologist at the University of Maryland School of Medicine, told me.
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In addition to proteins that help it replicate and the spike proteins that make up a portion of the virus’s outer capsule, SARS-CoV-2 has a set of relatively mysterious “accessory proteins” that are unique to this virus. Figuring out what these accessory proteins are doing, Frieman said, could help scientists figure out other ways SARS-CoV-2 interacts with the human cell. These accessory proteins might allow the virus to evade the human cell’s natural antiviral defense in some way—another potential target for a drug. “If you can target that process,” Frieman said, “you can help the cell inhibit the virus.”
Stop the immune system from going haywire
Antivirals are likely to work best early in an infection, when the virus has not infected many cells nor made too many copies of itself yet. “When you give antivirals too late, the risk is the immune component has already taken over,” Ott says. In COVID-19 specifically, patients who become critically and fatally ill seem to experience what’s known as a cytokine storm, in which the disease sets off an indiscriminate and runaway immune response. Perversely, cytokine storms can also further damage the lungs, sometimes permanently, by allowing fluid to build up in the tissue, says Stephen Gottschalk, an immunologist at St. Jude Children’s Research Hospital. Another way to treat COVID-19, then, is by treating the immune response, rather than the virus itself.