Are lab-made molecules better than antibodies?
Many scientists hope that mass-produced mimics of these antibodiesmight help treat people with COVID-19 or prevent them from falling ill after becoming infected.
The coronavirusmight be new, but nature long ago gave humans the tools to recognize it, at least on a microscopic scale: antibodies, Y-shaped immune proteins that can latch onto pathogens and block them from infiltrating cells. Millions of years of evolution have honed these proteins into the disease- fifighting weapons they are today. But in a span of justmonths, a combination of human and machine intelligence may have beaten Mother Nature at her own game. Using computational tools, a team of researchers at the University of Washington designed and built from scratch a molecule that, whenpitted against the coronavirus in the lab, can attack and sequester it at least as well as an antibody does. When spritzed up the noses of mice and hamsters, it also appears to protect animals from becoming seriously sick. This molecule, called a minibinder for its ability to glom onto the coronavirus, is petite and stable enough to be shipped en masse in a freeze-dried state. Bacteria can also be engineered to ch urn out these mini binders, potentially making them not only e ff ff ff ff ff f fe ct ive but also cheap and convenient. The team’s product is still in the very early stages of development, andwillnot be on the market anytime soon. But so far “it’s looking very promising,” said Lauren Carter, one of the researchers behind the project, which is led by biochemist David Baker. Eventually, healthy people might be able to self-administer the minibinders as a nasal spray, and potentially keep any inbound coronavirus particles at bay. “The most elegant application could be something you keep on your bedside table,” Carter said. “That’s kind of the dream.” Minibinders are not antibodies, but they thwart the virus inbroadly similarways. The coronavirus enters a cell using a kind of lock-and-key interaction, fifitting a protein calleda spike— the key— into a molecular lock called ACE -2, whichadorns the outsides of certain human cells. Antibodiesmade by the human immune system can interfere with this process. Many scientists hope that mass-produced mimics of these antibodies might help treat people with COVID-19 or prevent them from falling ill after becoming
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infected. But a lot of antibod
ies are needed to rein in the coronavirus, especially if an infection is underway. Antibodiesarealsooneroustoproduce and deliver to people.
To develop a less fifinicky alternative, members of the Baker lab, led by biochemist Longxing Cao, took a computational approach. The researchers modeled how millions of hypothetical, lab-d esigned proteins would interact with the spike. After sequentially weeding out poor performers, the team selected the best among the bunch and synthesized themin the lab. They spent weeks toggling between the computer andthebench, tinkeringwith designs tomatch simulation and reality as closely as they could. The result was a completely homemade minibinder that readily glued itself to the virus, the team reported in Science lastmonth. But the novelty of the minibinder approach could also be a drawback. It’s possible, for instance, that the coronavirus could mutate and become resistant to the DIY molecule. Daniel-Adriano Silva, a biochemist at Seatt le-base db io pharmaceutical company Neoleukin, who previously trained with Baker at the University of Washington, mayhave come upwithanother strategy that could solve the resistance problem. His teamhas alsodesigned a protein that can stop the virus frominvading cells, but theirDIYmolecule is slightly more familiar. It is a smaller, sturdier version of the human proteinACE-2— onethathasa far stronger griponthevirus, so themolecule couldpotentially serve as a decoy that lures the pathogen away from vulnerable cells. Both research groups are exploring their products as potential tools not only to combat infection but also to prevent it out right, somewhat like a short-lived vaccine. In a series of experiments described in their paper, the Ne oleuk in team misted their ACE -2 decoy into the noses of hamsters, then exposed the animals to the coronavirus. The untreated hamsters fell dangerously ill, but thehamsters that received the nasal spray fared far better. Carter and her colleagues are currently running similar experiments with their minibinder, andseeing comparable results. These fifindings might not translate into humans, the researchers cautioned. And neither team has yet worked out a perfectway to administer their products into animals or people. Downtheline, there may yet be opportunities for the two types of designer proteins towork together— if not in the same product, then at least in the same war, as the pandemic rages on. “It’ s very complementary ,” Carter said. If all goes well, molecules likethese couldjointhe growing arsenal of public health measures and drugs already in place to fifififight the virus, she said: “This is another tool you could have.”