That frailty is exactly what many researchers are counting on. Adam Zlotnick, a biophysicist at Indiana University Bloomington, specializes in disrupting virus assembly. An obvious strategy, he said, would be to introduce a drug or other treatment to slow or stop the building of new viruses. But he and his colleagues have found that using drugs to speed up the process can also prove disastrous. Unable to wriggle into the proper configuration, or to correct initial errors, the virus’s bits and pieces might glue together improperly, layering mistakes atop mistakes until the entire structure is malformed.
“If you make it go a little bit faster, that’s bad, you get more virus,” said Dr. Zlotnick, who compared the acceleration to the chaos that might unfold if an assembly line was moving too fast. “But a lot faster? It’s going to screw up and make defective particles.”
Dr. Zlotnick has spent much of his career working on the hepatitis B virus, and has helped to develop drugs that can foil the pathogen’s assembly process, some of which are now in clinical trials. Although the coronavirus is a very different beast, it could someday be vulnerable to the same general strategy, Dr. Zlotnick said.
Other researchers are eyeing another step in the virus-building pipeline: the generation of virus genes, before they are packaged into their protein capsules. Carlos Bustamante, a biophysicist at the University of California, Berkeley, is set on sabotaging a protein called polymerase, which copies the coronavirus’s genome.
The polymerase zooms over a stretch of RNA and replicates it letter for letter, a process that requires an intimate connection between the molecules and enough force to propel the protein. That force can be measured with a tiny set of “optical tweezers” — a laser that hooks on to one end of the polymerase, using a microscopic glass bead, and pulls in the direction opposite the protein’s path. “We are playing tug of war,” Dr. Bustamante said. “Every time it moves, it has to pull us.”
The hope, he said, is to understand the tug well enough to design a drug that blocks the RNA-copying process.
In Delaware, Dr. Perilla and Dr. Hadden-Perilla are studying a moment even earlier in the process, when the coronavirus enters a human cell and unravels its genome. This transforms the virus from a hardy infectious particle, which must move through the air and evade immune cells, into a naked and vulnerable template, unspooling itself for evaluation. The coronavirus “is a shape-shifter,” Dr. Hadden-Perilla said. But scientists don’t fully understand how the virus can tell when it’s time to disrobe.